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<div class="pre-content"><div><div class="bk_prnt"><p class="small">NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.</p><p>PDQ Cancer Information Summaries [Internet]. Bethesda (MD): National Cancer Institute (US); 2002-. </p></div><div class="iconblock clearfix whole_rhythm no_top_margin bk_noprnt"><a class="img_link icnblk_img" title="Table of Contents Page" href="/books/n/pdqcis/"><img class="source-thumb" src="/corehtml/pmc/pmcgifs/bookshelf/thumbs/th-pdqcis-lrg.png" alt="Cover of PDQ Cancer Information Summaries" height="100px" width="80px" /></a><div class="icnblk_cntnt eight_col"><h2>PDQ Cancer Information Summaries [Internet].</h2><a data-jig="ncbitoggler" href="#__NBK83261_dtls__">Show details</a><div style="display:none" class="ui-widget" id="__NBK83261_dtls__"><div>Bethesda (MD): <a href="http://www.cancer.gov/" ref="pagearea=page-banner&targetsite=external&targetcat=link&targettype=publisher">National Cancer Institute (US)</a>; 2002-.</div></div><div class="half_rhythm"></div><div class="bk_noprnt"><form method="get" action="/books/n/pdqcis/" id="bk_srch"><div class="bk_search"><label for="bk_term" class="offscreen_noflow">Search term</label><input type="text" title="Search this book" id="bk_term" name="term" value="" data-jig="ncbiclearbutton" /> <input type="submit" class="jig-ncbibutton" value="Search this book" submit="false" style="padding: 0.1em 0.4em;" /></div></form></div></div></div></div></div>
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<div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><h1 id="_NBK83261_"><span class="title" itemprop="name">Prostate Cancer, Nutrition, and Dietary Supplements (PDQ®)</span></h1><div class="subtitle whole_rhythm">Health Professional Version</div><p class="contrib-group"><span itemprop="author">PDQ Integrative, Alternative, and Complementary Therapies Editorial Board</span>.</p><p class="small">Published online: August 10, 2017.</p><p class="small">Created: <span itemprop="datePublished">January 6, 2012</span>.</p></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="_abs_rndgid_" itemprop="description"><p id="CDR0000719335__583">This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the use of nutrition and dietary supplements for reducing the risk of developing prostate cancer or for treating prostate cancer. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.</p><p id="CDR0000719335__584">This summary is reviewed regularly and updated as necessary by the PDQ Integrative, Alternative, and Complementary Therapies Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).</p></div><div id="CDR0000719335__47"><h2 id="_CDR0000719335__47_">Introduction</h2><p id="CDR0000719335__48">This <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045333/" class="def">cancer</a> information summary provides an overview of the use of various foods and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000373932/" class="def">dietary supplements</a> for reducing the risk of developing <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000445079/" class="def">prostate cancer</a> or for treating prostate cancer. This summary includes the history of research, reviews of laboratory and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000454774/" class="def">animal studies</a>, and results of <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045961/" class="def">clinical trials</a> on the following foods or dietary supplements:</p><ul id="CDR0000719335__245"><li class="half_rhythm"><div><a href="#CDR0000719335__426">Calcium</a>.</div></li><li class="half_rhythm"><div><a href="#CDR0000719335__174">Green tea</a>.</div></li><li class="half_rhythm"><div><a href="#CDR0000719335__16">Lycopene</a>.</div></li><li class="half_rhythm"><div><a href="#CDR0000719335__161">Modified citrus pectin</a>.</div></li><li class="half_rhythm"><div><a href="#CDR0000719335__162">Pomegranate</a>.</div></li><li class="half_rhythm"><div><a href="#CDR0000719335__283">Selenium</a>.</div></li><li class="half_rhythm"><div><a href="#CDR0000719335__163">Soy</a>.</div></li><li class="half_rhythm"><div><a href="#CDR0000719335__357">Vitamin D</a>.</div></li><li class="half_rhythm"><div><a href="#CDR0000719335__328">Vitamin E</a>.</div></li><li class="half_rhythm"><div><a href="#CDR0000719335__485">Multicomponent therapies</a>.</div></li><li class="half_rhythm"><div><a href="#CDR0000719335__387">Other prostate health supplements</a>.</div></li></ul><p id="CDR0000719335__246">Each type of dietary supplement or food will have a dedicated section in the summary, and new topics will be added over time. Note: A separate <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044271/" class="def">PDQ</a> summary on <a href="/books/n/pdqcis/CDR0000404384/">PC-SPES</a> is also available.</p><p id="CDR0000719335__49">Prostate cancer is the most common noncutaneous cancer affecting men in the United States. From 2008 to 2012, the <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044941/" class="def">median</a> age of <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046450/" class="def">diagnosis</a> of prostate cancer was 66, and the <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046145/" class="def">incidence</a> rate was 138 cases per 100,000 men per year.[<a class="bk_pop" href="#CDR0000719335_rl_47_1">1</a>]</p><p id="CDR0000719335__50">Many studies suggest that complementary and alternative medicine (CAM) use is common among prostate cancer patients, and the use of <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044744/" class="def">vitamins</a>, supplements, and specific foods is frequently reported by these patients. For example, the Prostate CAncer Therapy Selection (PCATS) study was a <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044079/" class="def">prospective</a> study that investigated men’s decision-making processes about treatment following a diagnosis of local-<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045885/" class="def">stage</a> prostate cancer. As part of this study, patients completed surveys regarding CAM use, and more than half of the respondents reported using one or more CAM therapies, with <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000729732/" class="def">mind-body modalities</a> and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044510/" class="def">biologically</a> based treatments being the most commonly used.[<a class="bk_pop" href="#CDR0000719335_rl_47_2">2</a>]</p><p id="CDR0000719335__51">International studies have reported similar findings. A Swedish study published in 2011 found that, overall, participants with prostate cancer were more likely to have used supplements than were healthy population-based <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044149/" class="def">control subjects</a>. Supplement use was even more common among patients with the healthiest dietary patterns (e.g., high consumption of fatty fish and vegetables).[<a class="bk_pop" href="#CDR0000719335_rl_47_3">3</a>] In a Canadian study, CAM use was reported among 39% of recently diagnosed prostate cancer patients, and the most commonly used forms of CAM were <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000463714/" class="def">herbals</a>, vitamins, and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045787/" class="def">minerals</a>. Within those categories, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000514413/" class="def">saw palmetto</a>, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045023/" class="def">vitamin E</a>, and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045113/" class="def">selenium</a> were the most popular. The two most popular reasons for choosing CAM were to boost the <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046356/" class="def">immune system</a> and to prevent <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045861/" class="def">recurrence</a>.[<a class="bk_pop" href="#CDR0000719335_rl_47_4">4</a>] According to another Canadian study, approximately 30% of survey respondents with prostate cancer reported using CAM treatments. In that study, vitamin E, saw palmetto, and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044909/" class="def">lycopene</a> were most commonly used.[<a class="bk_pop" href="#CDR0000719335_rl_47_5">5</a>] A British study published in 2008 indicated that 25% of prostate cancer patients used CAM, with the most frequently reported interventions being low-fat <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044660/" class="def">diets</a>, vitamins, and lycopene. The majority of CAM users in this study cited improving <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045417/" class="def">quality of life</a> and boosting the immune system as the main reasons they used CAM.[<a class="bk_pop" href="#CDR0000719335_rl_47_6">6</a>]</p><p id="CDR0000719335__52">Vitamin and supplement use has also been documented in men at risk of developing prostate cancer. One study examined vitamin and supplement use in men with a <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000302456/" class="def">family history</a> of prostate cancer. At the time of the survey, almost 60% of the men were using vitamins or supplements. One-third of the men were using vitamins and supplements that were specifically marketed for prostate health or <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045487/" class="def">chemoprevention</a> (e.g., selenium, green tea, and saw palmetto).[<a class="bk_pop" href="#CDR0000719335_rl_47_7">7</a>] A 2004 study examined herbal and vitamin supplement use in men who attended a prostate cancer <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000046171/" class="def">screening</a> clinic. Men who attended the screening clinic completed questionnaires about supplement use. Of the respondents, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000390238/" class="def">analysis</a> revealed that a reported 70% used multivitamins, and 21% used herbal supplements.[<a class="bk_pop" href="#CDR0000719335_rl_47_8">8</a>]</p><p id="CDR0000719335__53">A <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000691484/" class="def">meta-analysis</a> published in 2008 reviewed studies that reported vitamin and mineral supplement use among cancer <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000450125/" class="def">survivors</a>. The results showed that, among prostate cancer survivors, vitamin or mineral use ranged from 26% to 35%.[<a class="bk_pop" href="#CDR0000719335_rl_47_9">9</a>]</p><p id="CDR0000719335__54">Although many prostate cancer patients use CAM treatments, they do not all disclose their CAM use to treating physicians. According to results from the PCATS study, 43% of patients discussed their CAM use with a healthcare professional.[<a class="bk_pop" href="#CDR0000719335_rl_47_2">2</a>] In two separate studies, 58% of respondents told their doctors about their CAM usage.[<a class="bk_pop" href="#CDR0000719335_rl_47_4">4</a>,<a class="bk_pop" href="#CDR0000719335_rl_47_6">6</a>]</p><p id="CDR0000719335__55">How do prostate cancer patients decide whether or not to use CAM? A qualitative study published in 2005 described results from interviews with prostate cancer patients. The study identified differences in thinking patterns between CAM users and nonusers and suggested that no specific theme led patients to CAM; instead, patients were directed by a combination of ideas. For example, the perception of CAM as harmless was associated with the belief that <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000449752/" class="def">conventional medicine</a> resulted in many negative <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046580/" class="def">side effects</a>.[<a class="bk_pop" href="#CDR0000719335_rl_47_10">10</a>] Results of a 2003 qualitative study suggested that decision making about CAM treatments by prostate cancer patients depended on both fixed (e.g., medical history) and flexible (e.g., a need to feel in control) decision factors.[<a class="bk_pop" href="#CDR0000719335_rl_47_11">11</a>]</p><p id="CDR0000719335__577">Many of the medical and scientific terms used in this summary are hypertext linked (at first use in each section) to the <a href="https://www.cancer.gov/publications/dictionaries/cancer-terms/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NCI Dictionary of Cancer Terms</a>, which is oriented toward nonexperts. When a linked term is clicked, a definition will appear in a separate window.</p><p id="CDR0000719335__578">Reference citations in some PDQ cancer information summaries may include links to external websites that are operated by individuals or organizations for the purpose of marketing or advocating the use of specific treatments or products. These reference citations are included for informational purposes only. Their inclusion should not be considered an endorsement of the content of the websites, or of any treatment or product, by the PDQ Integrative, Alternative, and Complementary Therapies Editorial Board or the <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044266/" class="def">National Cancer Institute</a>.</p><div id="CDR0000719335_rl_47"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000719335_rl_47_1">National Cancer Institute: SEER Stat Fact Sheets: Prostate. Bethesda, MD: National Cancer Institute. <a href="https://seer.cancer.gov/statfacts/html/prost.html#prevalence" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">Available online</a>. Last accessed July 19, 2017.</div></li><li><div class="bk_ref" id="CDR0000719335_rl_47_2">McDermott CL, Blough DK, Fedorenko CR, et al.: Complementary and alternative medicine use among newly diagnosed prostate cancer patients. Support Care Cancer 20 (1): 65-73, 2012. [<a href="https://pubmed.ncbi.nlm.nih.gov/21120540" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21120540</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_47_3">Westerlund A, Steineck G, Bälter K, et al.: Dietary supplement use patterns in men with prostate cancer: the Cancer Prostate Sweden study. Ann Oncol 22 (4): 967-72, 2011. [<a href="https://pubmed.ncbi.nlm.nih.gov/20926547" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20926547</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_47_4">Eng J, Ramsum D, Verhoef M, et al.: A population-based survey of complementary and alternative medicine use in men recently diagnosed with prostate cancer. Integr Cancer Ther 2 (3): 212-6, 2003. [<a href="https://pubmed.ncbi.nlm.nih.gov/15035882" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15035882</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_47_5">Boon H, Westlake K, Stewart M, et al.: Use of complementary/alternative medicine by men diagnosed with prostate cancer: prevalence and characteristics. Urology 62 (5): 849-53, 2003. [<a href="https://pubmed.ncbi.nlm.nih.gov/14624907" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 14624907</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_47_6">Wilkinson S, Farrelly S, Low J, et al.: The use of complementary therapy by men with prostate cancer in the UK. Eur J Cancer Care (Engl) 17 (5): 492-9, 2008. [<a href="https://pubmed.ncbi.nlm.nih.gov/18637112" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18637112</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_47_7">Bauer CM, Ishak MB, Johnson EK, et al.: Prevalence and correlates of vitamin and supplement usage among men with a family history of prostate cancer. Integr Cancer Ther 11 (2): 83-9, 2012. [<a href="/pmc/articles/PMC3213317/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3213317</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/21821653" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21821653</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_47_8">Barqawi A, Gamito E, O'Donnell C, et al.: Herbal and vitamin supplement use in a prostate cancer screening population. Urology 63 (2): 288-92, 2004. [<a href="https://pubmed.ncbi.nlm.nih.gov/14972473" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 14972473</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_47_9">Velicer CM, Ulrich CM: Vitamin and mineral supplement use among US adults after cancer diagnosis: a systematic review. J Clin Oncol 26 (4): 665-73, 2008. [<a href="https://pubmed.ncbi.nlm.nih.gov/18235127" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18235127</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_47_10">Singh H, Maskarinec G, Shumay DM: Understanding the motivation for conventional and complementary/alternative medicine use among men with prostate cancer. Integr Cancer Ther 4 (2): 187-94, 2005. [<a href="https://pubmed.ncbi.nlm.nih.gov/15911931" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15911931</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_47_11">Boon H, Brown JB, Gavin A, et al.: Men with prostate cancer: making decisions about complementary/alternative medicine. Med Decis Making 23 (6): 471-9, 2003 Nov-Dec. [<a href="https://pubmed.ncbi.nlm.nih.gov/14672107" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 14672107</span></a>]</div></li></ol></div></div><div id="CDR0000719335__426"><h2 id="_CDR0000719335__426_">Calcium</h2><div id="CDR0000719335__537"><h3>Overview</h3><p id="CDR0000719335__538">This section contains the following key information:</p><ul id="CDR0000719335__539"><li class="half_rhythm"><div><a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045632/" class="def">Calcium</a> is required for certain <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044056/" class="def">metabolic</a> functions such as vascular contraction and vasodilation, muscle function, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000373935/" class="def">nerve</a> transmission, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044047/" class="def">intracellular</a> signaling, and hormonal secretion.</div></li><li class="half_rhythm"><div>Major sources of calcium in the United States are food and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000373932/" class="def">dietary supplements</a>.</div></li><li class="half_rhythm"><div>Studies of the association between calcium and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000445079/" class="def">prostate cancer</a> have been limited to <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044698/" class="def">nutritional</a> sources of calcium, such as dairy products.</div></li><li class="half_rhythm"><div>Some studies suggest that high total calcium intake may be associated with increased risk of advanced and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044058/" class="def">metastatic</a> prostate cancer, compared with lower intake of calcium.</div></li><li class="half_rhythm"><div>Additional research is needed to clarify the effects of calcium and/or dairy products on prostate cancer risk.</div></li></ul></div><div id="CDR0000719335__427"><h3>General Information and History</h3><p id="CDR0000719335__428">Calcium, the most abundant <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045787/" class="def">mineral</a> in the body, is found in some foods, added to others, available as a dietary supplement, and present in some <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000482419/" class="def">medicines</a> (such as antacids). Calcium is required for vascular contraction and vasodilation, muscle function, nerve transmission, intracellular signaling, and hormonal secretion, although less than 1% of total body calcium is needed to support these critical metabolic functions.[<a class="bk_pop" href="#CDR0000719335_rl_426_1">1</a>] <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044088/" class="def">Serum</a> calcium is very tightly regulated and does not fluctuate with changes in dietary intake; the body uses bone <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046683/" class="def">tissue</a> as a reservoir for, and source of, calcium to maintain constant concentrations of calcium in <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000270735/" class="def">blood</a>, muscle, and intercellular <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044669/" class="def">fluids</a>.[<a class="bk_pop" href="#CDR0000719335_rl_426_1">1</a>] </p><p id="CDR0000719335__534">The major sources of calcium in the U.S. population are food and dietary supplements.[<a class="bk_pop" href="#CDR0000719335_rl_426_2">2</a>] According to recent National Health and Nutrition Examination Survey data, U.S. adults obtain 38% of their dietary calcium from milk and milk products, such as yogurt and cheese.[<a class="bk_pop" href="#CDR0000719335_rl_426_3">3</a>] Nondairy sources include vegetables, such as Chinese cabbage, kale, and broccoli. Spinach provides calcium, but its <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044225/" class="def">bioavailability</a> is poor. Most grains do not have high amounts of calcium unless they are fortified; however, they contribute calcium to the <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044660/" class="def">diet</a> because they contain small amounts of calcium, and people consume them frequently. Foods fortified with calcium include many fruit juices and drinks, tofu, and cereals. In the United States, dietary supplements, including calcium supplements, are commonly used to prevent <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045641/" class="def">chronic</a> diseases, including <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045333/" class="def">cancer</a>.[<a class="bk_pop" href="#CDR0000719335_rl_426_1">1</a>] <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000285973/" class="def">Mean</a> dietary calcium intakes for males aged 1 year and older ranged from 871 to 1,266 mg/day depending on life stage group (i.e., infant, adolescent, or adult). About 43% of the U.S. population uses dietary supplements containing calcium, which increases calcium intake by about 330 mg/day among supplement users.[<a class="bk_pop" href="#CDR0000719335_rl_426_1">1</a>,<a class="bk_pop" href="#CDR0000719335_rl_426_2">2</a>]</p><p id="CDR0000719335__512">To evaluate the association between calcium intake and prostate cancer <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000496502/" class="def">mortality</a> and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044514/" class="def">morbidity</a>, it may be important to assess objective, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044510/" class="def">biological</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045776/" class="def">markers</a> of calcium, include data that account for nutritional and supplemental calcium intake, and control for other confounding factors. However, studies of association between calcium and prostate cancer have been limited to nutritional sources of calcium, such as dairy products. Although more than half of the U.S. population uses <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044744/" class="def">vitamin</a> and mineral supplements (at an annual cost of over 11 billion dollars), few studies include supplement use in the association of disease risk, including prostate cancer or mortality rates.[<a class="bk_pop" href="#CDR0000719335_rl_426_1">1</a>,<a class="bk_pop" href="#CDR0000719335_rl_426_2">2</a>] (Refer to the PDQ summary on <a href="/books/n/pdqcis/CDR0000062833/">Prostate Cancer Prevention</a> for more information.)</p></div><div id="CDR0000719335__513"><h3>Preclinical/Animal Studies</h3><div id="CDR0000719335__514"><h4><i>In vitro</i> studies</h4><p id="CDR0000719335__515"><a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046539/" class="def">Prostate</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000695994/" class="def">cancer cells</a> were treated with bovine milk, almond milk, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000407766/" class="def">soy</a> milk, casein, or <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044686/" class="def">lactose</a> in a 2011 study. Treatment with bovine milk resulted in growth stimulation of LNCaP prostate cancer cells. Growth of prostate cancer cells was not affected by treatment with soy milk, and treatment with almond milk resulted in growth inhibition.[<a class="bk_pop" href="#CDR0000719335_rl_426_4">4</a>]</p></div><div id="CDR0000719335__516"><h4><i>In vivo</i> studies</h4><p id="CDR0000719335__517">One study investigated the effects of dietary calcium on prostate <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045669/" class="def">tumor progression</a> in LPB-Tag <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000691466/" class="def">transgenic mice</a>. The animals consumed low (0.2%) or high (2.0%) calcium diets and were sacrificed at age 5, 7, or 9 weeks. <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046634/" class="def">Tumor</a> weight and progression were similar in mice that were fed low- and high-calcium diets.[<a class="bk_pop" href="#CDR0000719335_rl_426_5">5</a>]</p><p id="CDR0000719335__518">A 2012 study examined the impact of dietary <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000427253/" class="def">vitamin D</a> and calcium on prostate cancer growth in <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044579/" class="def">athymic mice</a>. The mice were <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044678/" class="def">injected</a> with human prostate cancer cells and were randomly assigned to receive specific diets (e.g., high calcium/vitamin D or normal calcium/no vitamin D). The mice that received the normal calcium/vitamin D-deficient diet exhibited significantly greater (<i>P</i> < .05) tumor volumes than did mice that received the other diets.[<a class="bk_pop" href="#CDR0000719335_rl_426_6">6</a>]</p></div></div><div id="CDR0000719335__436"><h3>Human Studies</h3><div id="CDR0000719335__437"><h4>Epidemiologic studies</h4><p id="CDR0000719335__520">Several <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000257225/" class="def">epidemiological</a> studies have found an association between high intakes of calcium, dairy foods, or both, and an increased risk of developing prostate cancer.[<a class="bk_pop" href="#CDR0000719335_rl_426_7">7</a>-<a class="bk_pop" href="#CDR0000719335_rl_426_9">9</a>] However, others have found only a weak relationship, no relationship, or a negative association between calcium intake and prostate cancer risk.[<a class="bk_pop" href="#CDR0000719335_rl_426_10">10</a>-<a class="bk_pop" href="#CDR0000719335_rl_426_13">13</a>] On the basis of these studies, interpretation of the evidence is complicated by the difficulty of separating the effects of dairy products from the effects of calcium. Additionally, earlier epidemiological studies had several limitations. The association of calcium intake with prostate cancer was limited to evidence from self-reported food frequency questionnaires of nutritional sources of calcium, with a focus on dairy foods.[<a class="bk_pop" href="#CDR0000719335_rl_426_14">14</a>,<a class="bk_pop" href="#CDR0000719335_rl_426_15">15</a>] Competing risk factors, such as other major <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044697/" class="def">nutrients</a> in dairy (i.e., fats) and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000635464/" class="def">concomitant</a> and confounding factors (i.e., age, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000455136/" class="def">body mass index</a>, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000613764/" class="def">steroid</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045713/" class="def">hormones</a>, and other metabolic events in the causal pathway) were not accounted for. Additionally, no objective markers of calcium, such as serum calcium, were obtained from these <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000561393/" class="def">cohorts</a>. <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000286105/" class="def">Observational studies</a> overall, however, suggest that high total calcium intake may be associated with increased risk of advanced and metastatic prostate cancer, compared with lower intake of calcium.[<a class="bk_pop" href="#CDR0000719335_rl_426_11">11</a>,<a class="bk_pop" href="#CDR0000719335_rl_426_12">12</a>,<a class="bk_pop" href="#CDR0000719335_rl_426_16">16</a>-<a class="bk_pop" href="#CDR0000719335_rl_426_18">18</a>] Another <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000390238/" class="def">analysis</a> of 886 <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045851/" class="def">prostatectomy</a> patients found an increased risk of being diagnosed with more <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046053/" class="def">aggressive</a> disease in men with higher calcium intakes.[<a class="bk_pop" href="#CDR0000719335_rl_426_19">19</a>] The hazard of disease <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045861/" class="def">recurrence</a> after <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045570/" class="def">surgical</a> treatment was increased in men with both very low and high calcium intakes. Additional research is needed to clarify the effects of calcium and/or dairy products on prostate cancer risk and elucidate potential biological mechanisms.</p></div><div id="CDR0000719335__451"><h4>Intervention studies</h4><p id="CDR0000719335__452">In a <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045858/" class="def">randomized clinical trial</a> published in 2005, 672 men received either 3 g of <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045239/" class="def">calcium carbonate</a> (1,200 <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044213/" class="def">mg</a> calcium) or <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046688/" class="def">placebo</a> daily for 4 years and were followed for 12 years. During the first 6 years of the study, there were significantly fewer prostate cancer cases in the calcium group compared with the placebo group. However, this difference was no longer <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044167/" class="def">statistically significant</a> at the 10-year evaluation.[<a class="bk_pop" href="#CDR0000719335_rl_426_20">20</a>]</p></div><div id="CDR0000719335__453"><h4>Meta-analyses</h4><p id="CDR0000719335__454">A <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000691484/" class="def">meta-analysis</a> published in 2005 reported that there may be an association between increased risk of prostate cancer and greater consumption of dairy products and calcium.[<a class="bk_pop" href="#CDR0000719335_rl_426_21">21</a>]</p><p id="CDR0000719335__455">A 2008 meta-analysis reviewed 45 observational studies and found no evidence of a link between dairy products and risk of prostate cancer.[<a class="bk_pop" href="#CDR0000719335_rl_426_22">22</a>] A meta-analysis of <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000285673/" class="def">cohort studies</a> published between 1996 and 2006 found a positive association between milk and dairy product consumption and risk of prostate cancer.[<a class="bk_pop" href="#CDR0000719335_rl_426_23">23</a>]</p><p id="CDR0000719335__521">In a recent review, the U.S. Preventive Services Task Force Evidence Syntheses, formerly Systematic Evidence Reviews, conducted meta-analyses using Mantel-Haenszel fixed effects models for overall cancer <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046145/" class="def">incidence</a>, cardiovascular disease incidence, and all-cause mortality. Vitamin D and/or calcium <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045916/" class="def">supplementation</a> showed no overall effect on cancer incidence and mortality, including prostate cancer.[<a class="bk_pop" href="#CDR0000719335_rl_426_3">3</a>] In a meta-analysis of the association of calcium without the coadministration of vitamin D, a reduced risk of prostate cancer was observed, although there were only a few events.[<a class="bk_pop" href="#CDR0000719335_rl_426_24">24</a>]</p><p id="CDR0000719335__548">In 2007, the World Cancer Research Fund/American Institute for Cancer Research reported that there was probable evidence that diets high in calcium increase the risk of prostate cancer and that there is limited suggestive evidence that milk and dairy products also increase the risk.[<a class="bk_pop" href="#CDR0000719335_rl_426_25">25</a>] Since publication, 18 additional studies that evaluated dairy or calcium intake and the risk of prostate cancer have been published. A 2015 meta-analysis of this literature concluded that high intakes of dairy products, milk, low-fat milk, cheese, total dietary calcium, and dairy calcium may increase prostate cancer risk.[<a class="bk_pop" href="#CDR0000719335_rl_426_26">26</a>] Supplemental calcium and nondairy calcium were not associated with an increased risk, although supplemental calcium was associated with an increased risk of fatal prostate cancer. The authors suggested that this association needs additional study. </p></div><div id="CDR0000719335__457"><h4>Current clinical trials</h4><p id="CDR0000719335__458">Check NCI’s list of cancer clinical trials for CAM clinical trials on <a href="https://www.cancer.gov/about-cancer/treatment/clinical-trials/search/results?protocolsearchid=12189791&vers=1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">calcium carbonate</a> and <a href="https://www.cancer.gov/about-cancer/treatment/clinical-trials/search/results?protocolsearchid=12189795&vers=1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">calcium citrate</a> that are actively enrolling patients.</p><p id="CDR0000719335__459">General information about clinical trials is also available from the <a href="https://www.cancer.gov/about-cancer/treatment/clinical-trials" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NCI website</a>.</p></div></div><div id="CDR0000719335_rl_426"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000719335_rl_426_1">Ross AC, Taylor CL, Yaktine AL, et al., eds.: Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: National Academies Press, 2011. <a href="https://www.ncbi.nlm.nih.gov/books/NBK56070/" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">Also available online</a>. Last accessed June 6, 2017. [<a href="https://pubmed.ncbi.nlm.nih.gov/21796828" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21796828</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_426_2">Lampe JW: Dairy products and cancer. J Am Coll Nutr 30 (5 Suppl 1): 464S-70S, 2011. [<a href="https://pubmed.ncbi.nlm.nih.gov/22081693" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22081693</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_426_3">Fortmann SP, Burda BU, Senger CA, et al.: Vitamin, Mineral, and Multivitamin Supplements for the Primary Prevention of Cardiovascular Disease and Cancer: A Systematic Evidence Review for the U.S. Preventive Services Task Force. Rockville, MD: Agency for Healthcare Research and Quality, 2013. <a href="https://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0060787/" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">Available online</a>. Last accessed June 6, 2017. [<a href="https://pubmed.ncbi.nlm.nih.gov/24308073" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24308073</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_426_4">Tate PL, Bibb R, Larcom LL: Milk stimulates growth of prostate cancer cells in culture. Nutr Cancer 63 (8): 1361-6, 2011. [<a href="https://pubmed.ncbi.nlm.nih.gov/22043817" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22043817</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_426_5">Mordan-McCombs S, Brown T, Zinser G, et al.: Dietary calcium does not affect prostate tumor progression in LPB-Tag transgenic mice. J Steroid Biochem Mol Biol 103 (3-5): 747-51, 2007. [<a href="/pmc/articles/PMC1950667/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1950667</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/17307354" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17307354</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_426_6">Ray R, Banks M, Abuzahra H, et al.: Effect of dietary vitamin D and calcium on the growth of androgen-insensitive human prostate tumor in a murine model. Anticancer Res 32 (3): 727-31, 2012. [<a href="/pmc/articles/PMC4681513/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4681513</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/22399584" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22399584</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_426_7">Butler LM, Wong AS, Koh WP, et al.: Calcium intake increases risk of prostate cancer among Singapore Chinese. Cancer Res 70 (12): 4941-8, 2010. [<a href="/pmc/articles/PMC4219618/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4219618</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/20516117" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20516117</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_426_8">Kurahashi N, Inoue M, Iwasaki M, et al.: Dairy product, saturated fatty acid, and calcium intake and prostate cancer in a prospective cohort of Japanese men. Cancer Epidemiol Biomarkers Prev 17 (4): 930-7, 2008. [<a href="https://pubmed.ncbi.nlm.nih.gov/18398033" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18398033</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_426_9">Raimondi S, Mabrouk JB, Shatenstein B, et al.: Diet and prostate cancer risk with specific focus on dairy products and dietary calcium: a case-control study. Prostate 70 (10): 1054-65, 2010. [<a href="https://pubmed.ncbi.nlm.nih.gov/20232354" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20232354</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_426_10">Park Y, Mitrou PN, Kipnis V, et al.: Calcium, dairy foods, and risk of incident and fatal prostate cancer: the NIH-AARP Diet and Health Study. Am J Epidemiol 166 (11): 1270-9, 2007. [<a href="https://pubmed.ncbi.nlm.nih.gov/18000020" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18000020</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_426_11">Giovannucci E, Liu Y, Stampfer MJ, et al.: A prospective study of calcium intake and incident and fatal prostate cancer. Cancer Epidemiol Biomarkers Prev 15 (2): 203-10, 2006. [<a href="https://pubmed.ncbi.nlm.nih.gov/16492906" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16492906</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_426_12">Koh KA, Sesso HD, Paffenbarger RS Jr, et al.: Dairy products, calcium and prostate cancer risk. Br J Cancer 95 (11): 1582-5, 2006. [<a href="/pmc/articles/PMC2360740/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2360740</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/17106437" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17106437</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_426_13">Ahn J, Albanes D, Peters U, et al.: Dairy products, calcium intake, and risk of prostate cancer in the prostate, lung, colorectal, and ovarian cancer screening trial. Cancer Epidemiol Biomarkers Prev 16 (12): 2623-30, 2007. [<a href="https://pubmed.ncbi.nlm.nih.gov/18086766" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18086766</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_426_14">Park SY, Murphy SP, Wilkens LR, et al.: Calcium, vitamin D, and dairy product intake and prostate cancer risk: the Multiethnic Cohort Study. Am J Epidemiol 166 (11): 1259-69, 2007. [<a href="https://pubmed.ncbi.nlm.nih.gov/17925283" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17925283</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_426_15">Pettersson A, Kasperzyk JL, Kenfield SA, et al.: Milk and dairy consumption among men with prostate cancer and risk of metastases and prostate cancer death. Cancer Epidemiol Biomarkers Prev 21 (3): 428-36, 2012. [<a href="/pmc/articles/PMC3297731/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3297731</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/22315365" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22315365</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_426_16">Mitrou PN, Albanes D, Weinstein SJ, et al.: A prospective study of dietary calcium, dairy products and prostate cancer risk (Finland). Int J Cancer 120 (11): 2466-73, 2007. [<a href="https://pubmed.ncbi.nlm.nih.gov/17278090" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17278090</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_426_17">Kesse E, Bertrais S, Astorg P, et al.: Dairy products, calcium and phosphorus intake, and the risk of prostate cancer: results of the French prospective SU.VI.MAX (Supplémentation en Vitamines et Minéraux Antioxydants) study. Br J Nutr 95 (3): 539-45, 2006. [<a href="https://pubmed.ncbi.nlm.nih.gov/16512941" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16512941</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_426_18">Rohrmann S, Platz EA, Kavanaugh CJ, et al.: Meat and dairy consumption and subsequent risk of prostate cancer in a US cohort study. Cancer Causes Control 18 (1): 41-50, 2007. [<a href="https://pubmed.ncbi.nlm.nih.gov/17315319" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17315319</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_426_19">Binder M, Shui IM, Wilson KM, et al.: Calcium intake, polymorphisms of the calcium-sensing receptor, and recurrent/aggressive prostate cancer. Cancer Causes Control 26 (12): 1751-9, 2015. [<a href="/pmc/articles/PMC4633306/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4633306</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/26407952" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26407952</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_426_20">Baron JA, Beach M, Wallace K, et al.: Risk of prostate cancer in a randomized clinical trial of calcium supplementation. Cancer Epidemiol Biomarkers Prev 14 (3): 586-9, 2005. [<a href="https://pubmed.ncbi.nlm.nih.gov/15767334" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15767334</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_426_21">Gao X, LaValley MP, Tucker KL: Prospective studies of dairy product and calcium intakes and prostate cancer risk: a meta-analysis. J Natl Cancer Inst 97 (23): 1768-77, 2005. [<a href="https://pubmed.ncbi.nlm.nih.gov/16333032" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16333032</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_426_22">Huncharek M, Muscat J, Kupelnick B: Dairy products, dietary calcium and vitamin D intake as risk factors for prostate cancer: a meta-analysis of 26,769 cases from 45 observational studies. Nutr Cancer 60 (4): 421-41, 2008. [<a href="https://pubmed.ncbi.nlm.nih.gov/18584476" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18584476</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_426_23">Qin LQ, Xu JY, Wang PY, et al.: Milk consumption is a risk factor for prostate cancer in Western countries: evidence from cohort studies. Asia Pac J Clin Nutr 16 (3): 467-76, 2007. [<a href="https://pubmed.ncbi.nlm.nih.gov/17704029" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17704029</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_426_24">Bristow SM, Bolland MJ, MacLennan GS, et al.: Calcium supplements and cancer risk: a meta-analysis of randomised controlled trials. Br J Nutr 110 (8): 1384-93, 2013. [<a href="https://pubmed.ncbi.nlm.nih.gov/23601861" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23601861</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_426_25">Food, Nutrition, Physical Activity, and the Prevention of Cancer: A Global Perspective. Washington, DC: World Cancer Research Fund/American Institute for Cancer Research, 2007. <a href="http://www.aicr.org/assets/docs/pdf/reports/Second_Expert_Report.pdf" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">Also available online</a>. Last accessed August 3, 2017.</div></li><li><div class="bk_ref" id="CDR0000719335_rl_426_26">Aune D, Navarro Rosenblatt DA, Chan DS, et al.: Dairy products, calcium, and prostate cancer risk: a systematic review and meta-analysis of cohort studies. Am J Clin Nutr 101 (1): 87-117, 2015. [<a href="https://pubmed.ncbi.nlm.nih.gov/25527754" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25527754</span></a>]</div></li></ol></div></div><div id="CDR0000719335__174"><h2 id="_CDR0000719335__174_">Green Tea</h2><div id="CDR0000719335__175"><h3>Overview</h3><p id="CDR0000719335__176">This section contains the following key information:</p><ul id="CDR0000719335__177"><li class="half_rhythm"><div>All tea originates from the <i>Camellia sinensis</i> (L.) Kuntze plant, and the methods by which the leaves are processed determine the type of tea produced. For green tea, the leaves are steamed and dried.</div></li><li class="half_rhythm"><div>Some <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000651211/" class="def">research</a> suggests that green tea may have a protective effect against <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044005/" class="def">cardiovascular</a> disease and against various forms of <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045333/" class="def">cancer</a>, including <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000445079/" class="def">prostate cancer</a>.</div></li><li class="half_rhythm"><div><a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000686469/" class="def">Catechins</a> are <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000256573/" class="def">polyphenol</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000422394/" class="def">compounds</a> in tea that are associated with many of tea’s proposed health benefits. </div></li><li class="half_rhythm"><div>Green tea catechins (GTCs) include (−)-epigallocatechin-3-gallate (<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000687277/" class="def">EGCG</a>), (−)-epicatechin (EC), (−)-epigallocatechin (EGC), (−)-epicatechin-3-gallate (ECG), and oligomeric proanthocyanidins derived from these catechin <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000601171/" class="def">monomers</a>. </div></li><li class="half_rhythm"><div><a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044512/" class="def">Laboratory</a>, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044517/" class="def">preclinical</a>, and early-phase <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045961/" class="def">clinical trials</a> have identified EGCG as one of the most potent modulators of <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000561605/" class="def">molecular pathways</a> thought to be relevant to <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046539/" class="def">prostate</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046487/" class="def">carcinogenesis</a>. EGCG has been shown to act as an <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045592/" class="def">androgen</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000350250/" class="def">antagonist</a> and can suppress prostate cancer <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046479/" class="def">cell proliferation</a>, suppress production of <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046540/" class="def">prostate-specific antigen</a> (PSA) by prostate cancer <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046476/" class="def">cells</a>, and demonstrate potent and selective proapoptotic activity in prostate cancer <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000695994/" class="def">cell lines</a>
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<i><a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045733/" class="def">in vitro</a>.</i></div></li><li class="half_rhythm"><div><a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044068/" class="def">Oral</a> intake of either a GTC solution or EGCG alone was associated with significant reductions in <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046634/" class="def">tumor</a> size, reduced <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000372933/" class="def">multiplicity</a>, and reduced development of prostate cancer in studies with <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000691466/" class="def">transgenic</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046216/" class="def">adenocarcinoma</a> of the mouse prostate (TRAMP) mice.</div></li><li class="half_rhythm"><div>In Asian countries with a high <i>per capita</i> consumption of green tea, prostate cancer <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000496502/" class="def">mortality</a> rates are among the lowest in the world, and the risk of prostate cancer appears to be increased among Asian men who abandon their original dietary habits upon migrating to the United States. <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000348989/" class="def">Case-control</a> and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000285673/" class="def">cohort studies</a>, so far, have variously shown beneficial or neutral results, with the exception of one study that has shown an increased risk of the developing advanced prostate cancer with consumption of green tea.</div></li><li class="half_rhythm"><div>GTCs have been well tolerated in <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044195/" class="def">clinical studies</a> that target disease-free men, men with precursor <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046324/" class="def">lesions</a>, and men with prostate cancer. <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046580/" class="def">Side effects</a> were reduced with a decaffeinated formulation and when green tea was consumed in nonfasting conditions. The most common side effects related to GTC were mild <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045692/" class="def">gastrointestinal</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045022/" class="def">symptoms</a>.</div></li><li class="half_rhythm"><div>At least two <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045858/" class="def">randomized</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044014/" class="def">controlled</a> trials have shown an overall decreased rate of <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044078/" class="def">progression</a> to atypical small acinar proliferation or prostate cancer in men with <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000386205/" class="def">high-grade</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044345/" class="def">prostatic intraepithelial neoplasia</a> (HGPIN) treated with GTCs.</div></li></ul></div><div id="CDR0000719335__178"><h3>General Information and History</h3><p id="CDR0000719335__179">Sailors first brought tea to England in 1644, although tea has been popular in Asia since ancient times. After water, tea is the most-consumed beverage in the world.[<a class="bk_pop" href="#CDR0000719335_rl_174_1">1</a>] Tea originates from the <i>C. sinensis</i> plant, and the methods by which the leaves are processed determine the type of tea produced. Green tea is not fermented but is made by an <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046081/" class="def">enzyme</a> deactivation step whereby intensive heat (i.e., roasting the freshly collected tea leaves in a wok or, historically, steaming the leaves) is applied to preserve the tea's <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000256573/" class="def">polyphenols</a> (catechins) and freshness. In contrast, the enzyme-catalyzed polymerization and oxidation of catechins and other components produces darker-colored black tea.[<a class="bk_pop" href="#CDR0000719335_rl_174_2">2</a>] Oolong, a third major type of tea, contains polyphenols that are partially oxidized.[<a class="bk_pop" href="#CDR0000719335_rl_174_1">1</a>]</p><p id="CDR0000719335__256">In this PDQ information summary, “tea” refers to the leaves of the <i>C. sinensis</i> plant or the beverage brewed from those leaves.</p><p id="CDR0000719335__180">Some observational and interventional studies suggest that green tea may have a protective effect against cardiovascular disease,[<a class="bk_pop" href="#CDR0000719335_rl_174_3">3</a>] and there is evidence that green tea may protect against various forms of cancer.[<a class="bk_pop" href="#CDR0000719335_rl_174_4">4</a>] Many of the health benefits associated with tea have been attributed to polyphenols. GTCs include EGCG, EC, EGC, ECG, and oligomeric proanthocyanidins derived from these catechin monomers. Among these compounds, EGCG is the most abundant catechin in green tea and has been widely researched.[<a class="bk_pop" href="#CDR0000719335_rl_174_5">5</a>] Laboratory, preclinical, and early-phase clinical trials have identified EGCG as one of the most potent modulators of molecular pathways thought to be relevant to prostate carcinogenesis.[<a class="bk_pop" href="#CDR0000719335_rl_174_5">5</a>] Tea leaves also contain considerable amounts of oligomeric catechins, in particular, oligomeric proanthocyanidins. Together with the catechin monomers, they constitute the green tea polyphenols (GTPs). GTP composition varies widely, depending on processing and source of the tea leaves.</p></div><div id="CDR0000719335__185"><h3>Preclinical/Animal Studies</h3><div id="CDR0000719335__186"><h4><i>In vitro</i> studies</h4><p id="CDR0000719335__187">Prostate cancer cells treated with EGCG (concentrations, 0–80 <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000659790/" class="def">μM</a>) demonstrated suppressed cell proliferation and decreased levels of PSA <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046092/" class="def">protein</a> and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000662001/" class="def">mRNA</a> in the presence or absence of androgen.[<a class="bk_pop" href="#CDR0000719335_rl_174_6">6</a>]</p><p id="CDR0000719335__188">In a 2011 study, human prostate cancer cells were treated initially with EGCG (concentrations, 1.5–7.5 μM) and then with radiation. The results showed that exposing cells to EGCG for 30 minutes before radiation significantly reduced <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046524/" class="def">apoptosis</a>, compared with radiation alone.[<a class="bk_pop" href="#CDR0000719335_rl_174_7">7</a>]</p><p id="CDR0000719335__189">In another study, prostate cancer cells treated with EGCG (0–50 μM) exhibited <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044110/" class="def">dose-dependent</a> decreases in cellular proliferation and increases in extracellular signal-regulated <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000641114/" class="def">kinase</a> (ERK) 1/2 activity. To further examine the effect of EGCG on the ERK 1/2 pathway, cells were treated with EGCG (0–50 μM) and a mitogen-activated protein kinase (<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000600473/" class="def">MEK</a>) inhibitor or phosphoinositide-3 kinase (<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000530323/" class="def">PI3K</a>) inhibitor. Inhibition of MEK did not prevent ERK 1/2 upregulation, although the increase in ERK 1/2 after EGCG treatment was partially inhibited with the PI3K inhibitor. These findings suggest that EGCG may prevent prostate cancer cell proliferation by increasing the activity of ERK 1/2 via a MEK-independent, PI3K-dependent mechanism.[<a class="bk_pop" href="#CDR0000719335_rl_174_8">8</a>]</p><p id="CDR0000719335__190">According to a 2010 study, EGCG treatment (20–120 μM) resulted in changes in expression levels of 40 <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000045693/" class="def">genes</a> in prostate cancer cells, including a fourfold downregulation of inhibitor of <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000045671/" class="def">DNA</a> binding 2 (ID2; a protein involved in cell proliferation and survival). In addition, forced expression of ID2 in cells treated with 80 μM EGCG resulted in reduced apoptosis, suggesting that EGCG may cause cell death via an ID2-related mechanism.[<a class="bk_pop" href="#CDR0000719335_rl_174_9">9</a>]</p><p id="CDR0000719335__191">Advances in nanotechnology—“nanochemoprevention”—may result in more-effective <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000478733/" class="def">administration</a> of EGCG to men at risk of developing prostate cancer. Prostate cancer cells were treated with EGCG-loaded (100 μM EGCG) nanoparticles or free EGCG. Although both treatments decreased cell proliferation and induced apoptosis, the <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000653131/" class="def">nanoparticle</a> treatment had a greater effect at a lower <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000683342/" class="def">concentration</a> than did free EGCG. This finding suggests that using a nanoparticle delivery system for EGCG may increase its <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044225/" class="def">bioavailability</a> and improve its <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045487/" class="def">chemopreventive</a> actions.[<a class="bk_pop" href="#CDR0000719335_rl_174_10">10</a>] In one study, EGCG (30 μM) was <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046437/" class="def">encapsulated</a> in nanoparticles that contained polymers targeting prostate-specific <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046294/" class="def">membrane</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046086/" class="def">antigen</a> (PSMA). Prostate cancer cells treated with this <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000454757/" class="def">intervention</a> exhibited decreases in proliferation; however, the intervention did not affect <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044217/" class="def">nonmalignant</a> control cells. The results suggest that this delivery system may be effective for selective targeting of prostate cancer cells.[<a class="bk_pop" href="#CDR0000719335_rl_174_11">11</a>]</p><p id="CDR0000719335__192">Research also suggests that <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000373012/" class="def">glutathione-S-transferase</a> pi (GSTP1) may be a <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046657/" class="def">tumor suppressor</a> and that hypermethylation of certain regions of this gene (i.e., CpG islands) may be a <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000579630/" class="def">molecular marker</a> of prostate cancer. Increased <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000655031/" class="def">methylation</a> leads to silencing of the gene. A set of experiments investigated the effects of green tea polyphenols on GSTP1 expression. Treatment of different types of prostate cancer cells with green tea polyphenols (1–10 <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000306521/" class="def">μg</a>/<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000655103/" class="def">mL</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000350240/" class="def">Polyphenon E</a>) resulted in re-expression of GSTP1 by reversing hypermethylation and by reducing expression of methyl-CpG–binding <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000460145/" class="def">domain</a> proteins, which bind to methylated DNA. These results indicate that green tea polyphenols may have chemopreventive effects via actions on gene-silencing processes.[<a class="bk_pop" href="#CDR0000719335_rl_174_12">12</a>]</p><p id="CDR0000719335__193">The results of a 2011 study suggested that green tea polyphenols may exert anticancer effects by inhibiting <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000318814/" class="def">histone</a> deacetylases (<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000586370/" class="def">HDACs</a>). Class I HDACs are often overexpressed in various cancers, including prostate cancer. Treatment of human prostate cancer cells with green tea polyphenols (10–80 μg/mL Polyphenon E) resulted in decreased class I HDAC activity and increased expression of Bax, a proapoptotic protein.[<a class="bk_pop" href="#CDR0000719335_rl_174_13">13</a>]</p><p id="CDR0000719335__194">Owing to the high concentrations of tea polyphenols used in some of the <i>in vitro</i> experiments, results should be interpreted with caution. Studies in humans have indicated that <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000270735/" class="def">blood</a> levels of EGCG are 0.1 to 0.6 µM after consumption of two to three cups of green tea and that drinking seven to nine cups of green tea results in EGCG blood levels still lower than 1 μM.[<a class="bk_pop" href="#CDR0000719335_rl_174_14">14</a>,<a class="bk_pop" href="#CDR0000719335_rl_174_15">15</a>]</p></div><div id="CDR0000719335__195"><h4>Animal studies</h4><p id="CDR0000719335__196"><a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000043996/" class="def">Animal models</a> have been used in several studies investigating the effects of green tea on prostate cancer. In one study, TRAMP mice were given access to water or GTC–treated water (0.3% GTC solution; this exposure mimics human consumption of 6 cups of green tea daily). After 24 weeks, water-fed TRAMP mice had developed prostate cancer, whereas mice treated with GTCs showed only prostatic intraepithelial neoplasia lesions, suggesting that GTCs may help delay the development of prostate tumors.[<a class="bk_pop" href="#CDR0000719335_rl_174_16">16</a>] In another study, castrated mice were <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044678/" class="def">injected</a> with prostate cancer cells and then treated daily with <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046339/" class="def">intraperitoneal</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044678/" class="def">injections</a> of 1 <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044213/" class="def">mg</a> EGCG or vehicle. Treatment with EGCG resulted in reductions in <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000467873/" class="def">tumor volume</a> and decreases in serum PSA levels compared with vehicle treatment.</p><p id="CDR0000719335__197">In a 2011 study, EGCG was shown to be an androgen antagonist; when added to prostate cancer cells, EGCG physically interacted with the androgen receptor’s ligand-binding domain. In addition, mice <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000285636/" class="def">implanted</a> with tumor cells and treated with EGCG (intraperitoneal injections of 1 mg EGCG, 3/wk) exhibited less androgen receptor <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000557359/" class="def">protein expression</a> than did mice that were treated with vehicle.[<a class="bk_pop" href="#CDR0000719335_rl_174_17">17</a>]</p><p id="CDR0000719335__198">In a 2009 study, TRAMP mice were started on a green tea polyphenol intervention (0.1% green tea polyphenols in drinking water) at various ages (meant to represent different <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045885/" class="def">stages</a> of prostate cancer development).[<a class="bk_pop" href="#CDR0000719335_rl_174_18">18</a>] The results showed that, although all of the green tea–fed mice exhibited longer tumor-free survival than did water-fed control mice, there was an advantage for the mice that were fed with green tea the longest.[<a class="bk_pop" href="#CDR0000719335_rl_174_18">18</a>] In one study, EGCG treatment (0.06% EGCG in drinking water; this exposure mimics human consumption of 6 cups of green tea daily) was initiated in TRAMP mice at age 12 or 28 weeks. EGCG treatment suppressed HGPIN in mice treated at age 12 weeks; however, EGCG did not prevent prostate cancer development in mice that began treatment at age 28 weeks.[<a class="bk_pop" href="#CDR0000719335_rl_174_19">19</a>] </p><p id="CDR0000719335__618">Using the TRAMP mice model,[<a class="bk_pop" href="#CDR0000719335_rl_174_20">20</a>] one study demonstrated that oral infusion of GTP extract at a human-achievable dose (equivalent to 6 cups of green tea/d) significantly delayed primary tumor incidence and tumor burden, as assessed sequentially by <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045997/" class="def">magnetic resonance imaging</a>; decreased prostate weight (64% of baseline) and genitourinary weight (72%); inhibited serum insulin-like growth factor-1; restored insulin-like growth factor–binding protein-3 (IGFBP-3) levels; and produced marked reduction in the protein expression of proliferating cell nuclear antigen in the GTP-fed TRAMP mice, compared with water-fed TRAMP mice. Furthermore, GTP consumption caused significant apoptosis, which possibly resulted in reduced dissemination of cancer cells, thereby causing inhibition of development, progression, and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046710/" class="def">metastasis</a> to distant organ sites. In another study, 119 male TRAMP mice and 119 C57BL/6J mice were treated orally with one of three doses of Polyphenon E (200, 500, or 1,000 mg/kg/d) in drinking water <i>ad libitum</i>, replicating human-achievable doses. Safety and efficacy assessments were performed at baseline and when mice were 12, 22, and 32 weeks old. Results indicated that the number and size of tumors in treated TRAMP mice were significantly decreased, compared with untreated animals. In untreated 32-week-old TRAMP mice, prostate carcinoma metastasis to distant sites was observed in 100% of mice (8/8), compared with 13% of mice (2/16) treated with high-dose Polyphenon E during the same period.[<a class="bk_pop" href="#CDR0000719335_rl_174_21">21</a>]</p></div><div id="CDR0000719335__258"><h4>Animal safety studies</h4><p id="CDR0000719335__595">In a <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044266/" class="def">National Cancer Institute</a> (NCI) Division of Cancer Prevention (DCP)–sponsored, 9-month, oral <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000445093/" class="def">toxicity</a> study, Polyphenon E was administered (200, 500, or 1,000 mg/kg per day) to fasted male and female beagle dogs. The study was terminated prematurely because of excessive loss of animals due to <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044514/" class="def">morbidity</a> and mortality in all treatment groups. These studies have revealed some unique <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044170/" class="def">dose-limiting</a> lethal liver, gastrointestinal, and renal toxicities. Gross necropsy revealed therapy-induced lesions in the gastrointestinal tracts, livers, kidneys, reproductive organs, and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044036/" class="def">hematopoietic tissues</a> of treated male and female dogs. In the 13-week <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044671/" class="def">follow-up</a> study, the no-observed-adverse-effect–level was greater than 600 mg/kg per day of Polyphenon E.[<a class="bk_pop" href="#CDR0000719335_rl_174_22">22</a>] When the study was conducted in nonfasted dogs under the same testing conditions and dose levels, the results were unremarkable. Nonspecific toxicity and a tenfold reduction in the <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000546597/" class="def">maximum tolerated dose</a> in fasted beagle dogs compared with fed beagle dogs were seen using a purified GTC containing less than 77% EGCG.[<a class="bk_pop" href="#CDR0000719335_rl_174_23">23</a>] However, in the follow-up NCI DCP–sponsored study in fed dogs compared with fasted dogs using several Polyphenon E formulations, no deaths occurred, suggesting that fasting may have rendered the target organ systems more vulnerable to the effects of <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000389271/" class="def">green tea extract</a>.</p><p id="CDR0000719335__259"> In a study [<a class="bk_pop" href="#CDR0000719335_rl_174_21">21</a>] of several doses of a standardized Polyphenon E targeting TRAMP mice, no <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046312/" class="def">liver</a> or other toxicities were observed. Long-term (32 weeks) treatment with Polyphenon E (200, 500, and 1,000 mg/kg per day) was safe and well tolerated, with no evidence of toxicity in C57BL/6J mice. The C57BL/6J mice showed no differences in appearance or behavior, or changes in prostate and body weights after 32 weeks of treatment for all three doses of Polyphenon E. No discernible <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000467841/" class="def">histopathological</a> changes were observed in the liver, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000270740/" class="def">lung</a>, or any prostate <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046188/" class="def">lobe</a> of C57BL/6J mice treated with the three different doses of Polyphenon E. [<a class="bk_pop" href="#CDR0000719335_rl_174_21">21</a>] Similarly, another preclinical study [<a class="bk_pop" href="#CDR0000719335_rl_174_24">24</a>] did not observe liver or other toxicities with standardized EGCG at doses of up to 500 mg EGCG preparation/kg per day. </p></div></div><div id="CDR0000719335__199"><h3>Human Studies</h3><div id="CDR0000719335__200"><h4>Epidemiologic studies</h4><p id="CDR0000719335__201">The relationship between green tea intake and prostate cancer has been examined in several <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000257225/" class="def">epidemiological</a> studies.</p><p id="CDR0000719335__202">A 2011 <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000691484/" class="def">meta-analysis</a> examined the consumption of green and black tea and prostate cancer risk. For green tea, seven <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000286105/" class="def">observational studies</a> were identified, and most were from Asia. The results indicated a <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044167/" class="def">statistically significant</a> inverse association between green tea consumption and prostate cancer risk in the three case-control studies, but no association was found in the four cohort studies. For black tea, no association was found between black tea consumption and prostate cancer risk. The inconsistent results reported in these <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000561718/" class="def">population studies</a> may be attributed to confounding factors that include consumption of salted or very hot tea, geographical location, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000439432/" class="def">tobacco</a> and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000463134/" class="def">alcohol</a> use, and other dietary differences.[<a class="bk_pop" href="#CDR0000719335_rl_174_25">25</a>-<a class="bk_pop" href="#CDR0000719335_rl_174_29">29</a>] In Asian countries with a high <i>per capita</i> consumption of green tea, prostate cancer mortality rates are among the lowest in the world,[<a class="bk_pop" href="#CDR0000719335_rl_174_30">30</a>] and the risk of prostate cancer appears to be increased among Asian men who abandon their original dietary habits upon migrating to the United States.[<a class="bk_pop" href="#CDR0000719335_rl_174_30">30</a>] Overall, findings from population studies suggest that green tea may help protect against prostate cancer in Asian populations.[<a class="bk_pop" href="#CDR0000719335_rl_174_31">31</a>,<a class="bk_pop" href="#CDR0000719335_rl_174_32">32</a>] Currently, there are no epidemiological studies in other populations examining the association between green tea consumption and prostate cancer risk or protection from risk. With the increasing consumption of green tea worldwide, including by the U.S. population, emerging data from ongoing studies will further contribute to defining the cancer preventive activity of green tea or GTCs. </p></div><div id="CDR0000719335__203"><h4>Intervention studies</h4><div id="CDR0000719335__596"><h5>Bioavailability</h5><p id="CDR0000719335__607"><a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045832/" class="def">Phase I/II</a> intervention studies to date have reported bioavailability of EGCG in plasma using single and repeated doses of EGCG, noting higher plasma EGCG concentrations in fasting conditions relative to fed conditions.[<a class="bk_pop" href="#CDR0000719335_rl_174_33">33</a>-<a class="bk_pop" href="#CDR0000719335_rl_174_35">35</a>] Studies using varying doses (400 mg, 800 mg EGCG) of GTCs and Polyphenon E administered in single and repeated dosing schedules for 3 to 6 weeks have reported <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044941/" class="def">median</a> maximum concentrations of EGCG ranging from 68.8 <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000285977/" class="def">ng</a>/mL to 390.36 ng/mL (refer to Table 1).[<a class="bk_pop" href="#CDR0000719335_rl_174_35">35</a>-<a class="bk_pop" href="#CDR0000719335_rl_174_37">37</a>] Not all individuals in the treatment arms of these and other studies [<a class="bk_pop" href="#CDR0000719335_rl_174_27">27</a>,<a class="bk_pop" href="#CDR0000719335_rl_174_38">38</a>,<a class="bk_pop" href="#CDR0000719335_rl_174_39">39</a>] had detectable levels of EGCG, indicating potential variation in individual absorption. Catechins other than EGCG were nondetectable or below quantifiable levels in the plasma in many trials.</p><p id="CDR0000719335__608">Tissue levels of catechins have also been quite variable when examined. Notably, catechin levels in prostate tissue were low to undetectable after the administration of Polyphenon E in one preprostatectomy study.[<a class="bk_pop" href="#CDR0000719335_rl_174_36">36</a>] An <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000390238/" class="def">analysis</a> of prostate tissue obtained from the green tea drinkers revealed that both <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000655031/" class="def">methylated</a> and nonmethylated forms of EGCG are found in the prostate following a short-term treatment with green tea, with 48% of EGCG in the methylated form.[<a class="bk_pop" href="#CDR0000719335_rl_174_36">36</a>] Methylated forms of EGCG are not as effective as EGCG in inhibiting cell proliferation and inducing apoptosis in prostate cancer cells, suggesting that methylation status of EGCG may affect the chemopreventive properties of green tea. Methylation status may be determined by <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000044805/" class="def">polymorphisms</a> of the <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044098/" class="def">catechol</a>-O-methyltransferase (COMT; the enzyme that methylates EGCG) gene.[<a class="bk_pop" href="#CDR0000719335_rl_174_40">40</a>]</p><div id="CDR0000719335__609" class="table"><h3><span class="title">Table 1. Peak Plasma EGCG Levels</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK83261.13/table/CDR0000719335__609/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__CDR0000719335__609_lrgtbl__"><table class="no_margin"><thead><tr><th colspan="1" rowspan="1" style="vertical-align:top;">Source</th><th colspan="1" rowspan="1" style="vertical-align:top;">EGCG Dose</th><th colspan="1" rowspan="1" style="vertical-align:top;">Condition</th><th colspan="1" rowspan="1" style="vertical-align:top;">Duration</th><th colspan="1" rowspan="1" style="vertical-align:top;">Median Plasma EGCG Concentration (ng/mL)</th></tr></thead><tbody><tr><td colspan="1" rowspan="2" style="vertical-align:top;">[<a class="bk_pop" href="#CDR0000719335_rl_174_35">35</a>]</td><td colspan="1" rowspan="1" style="vertical-align:top;">400 mg</td><td colspan="1" rowspan="1" style="vertical-align:top;">Fed, fasted</td><td colspan="1" rowspan="1" style="vertical-align:top;">4 wk</td><td colspan="1" rowspan="1" style="vertical-align:top;">155.4 (fed), 161.4 (fasted)</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">800 mg</td><td colspan="1" rowspan="1" style="vertical-align:top;">Fed, fasted</td><td colspan="1" rowspan="1" style="vertical-align:top;">4 wk</td><td colspan="1" rowspan="1" style="vertical-align:top;">287.6 (fed), 390.36 (fasted)</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">[<a class="bk_pop" href="#CDR0000719335_rl_174_36">36</a>]</td><td colspan="1" rowspan="1" style="vertical-align:top;">800 mg (in Polyphenon E)</td><td colspan="1" rowspan="1" style="vertical-align:top;">Fed</td><td colspan="1" rowspan="1" style="vertical-align:top;">3–6 wk</td><td colspan="1" rowspan="1" style="vertical-align:top;">68.8 </td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">[<a class="bk_pop" href="#CDR0000719335_rl_174_37">37</a>]</td><td colspan="1" rowspan="1" style="vertical-align:top;">2 mg/kg</td><td colspan="1" rowspan="1" style="vertical-align:top;">Fasted</td><td colspan="1" rowspan="1" style="vertical-align:top;">Single dose</td><td colspan="1" rowspan="1" style="vertical-align:top;">77.9 </td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">[<a class="bk_pop" href="#CDR0000719335_rl_174_39">39</a>]</td><td colspan="1" rowspan="1" style="vertical-align:top;">200 mg (twice a day)</td><td colspan="1" rowspan="1" style="vertical-align:top;">Fed</td><td colspan="1" rowspan="1" style="vertical-align:top;">1 y</td><td colspan="1" rowspan="1" style="vertical-align:top;">12.3 (SD, 24.8)</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">EGCG = (−)-Epigallocatechin-3-gallate; kg = kilogram(s); mg = milligram(s); mL = milliliter(s); ng = nanogram(s); SD = standard deviation; wk = week(s); y = year.</p></div></dd></dl></div></div></div></div><div id="CDR0000719335__204"><h5>Prevention</h5><p id="CDR0000719335__205">In a single-center Italian study, 60 men diagnosed with HGPIN were randomly assigned to receive GTC <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000455334/" class="def">capsules</a> (600 mg GTCs daily) or a <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046688/" class="def">placebo</a> every day for 1 year. After 6 months, 6 of the 30 men in the placebo group were diagnosed with prostate cancer, whereas none of the 30 subjects in the GTC group were diagnosed with prostate cancer. After 1 year, nine men in the placebo group and one man in the GTC group were diagnosed with prostate cancer (<i>P</i> < .01). These findings suggest that GTCs may help prevent prostate cancer in groups at high risk of the disease.[<a class="bk_pop" href="#CDR0000719335_rl_174_41">41</a>] In 2008, follow-up results to this study were published, indicating that the inhibitory effects of GTCs on prostate cancer progression were long-lasting.[<a class="bk_pop" href="#CDR0000719335_rl_174_42">42</a>] However, nearly all of the prostate cancer risk reduction in that study occurred at the 6-month <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045164/" class="def">biopsy</a>, suggesting that the results may have been biased by a nonrandom distribution of occult prostate cancer at baseline.[<a class="bk_pop" href="#CDR0000719335_rl_174_30">30</a>] No reduction in serum PSA was observed in the treatment arm of this study compared with placebo. </p><p id="CDR0000719335__619">A larger, multicenter, randomized trial (<a href="http://cancer.gov/clinicaltrials/search/view?version=healthprofessional&cdrid=598161" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NCT00596011</a>) in the United States studied 97 men with either HGPIN or atypical small acinar proliferation who received a GTC mixture (Polyphenon E, 200 mg, twice a day).[<a class="bk_pop" href="#CDR0000719335_rl_174_39">39</a>] Atypical small acinar proliferation is an entity that reflects a broad group of lesions of varying clinical significance with insufficient cytological or architectural atypia to establish a definitive <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046450/" class="def">diagnosis</a> of prostate cancer.[<a class="bk_pop" href="#CDR0000719335_rl_174_7">7</a>,<a class="bk_pop" href="#CDR0000719335_rl_174_31">31</a>] Results indicated that a daily intake of a standardized, decaffeinated catechin mixture containing 400 mg EGCG per day for 1 year, accumulated in the plasma, was well tolerated,[<a class="bk_pop" href="#CDR0000719335_rl_174_39">39</a>]<a href="/books/n/pdqcis/glossary_loe/def-item/glossary_loe_CDR0000659430/" class="def">Level of evidence 1A</a> but did not significantly reduce the incidence of prostate cancer in the treatment group with Polyphenon E (5/49, 10.2%) compared with the placebo group (9/48, 18.8%; <i>P</i> = .25). However, in a prespecified secondary analysis performed in men with HGPIN (without atypical small acinar proliferation) at baseline, Polyphenon E was associated with a significant decrease in the composite endpoint (prostate cancer plus atypical small acinar proliferation) (3/26 Polyphenon E vs. 10/25 placebo, <i>P</i> < .024), with these findings largely driven by the absence of atypical small acinar proliferation on end-of-study biopsy on the Polyphenon E arm (Polyphenon E [0/26] vs. placebo arm [5/25]). Because there is no clear evidence that HGPIN and atypical small acinar proliferation represent steps on a linear path to prostate cancer, these findings should be interpreted with caution. A comparison of the estimated overall treatment effect showed a significantly greater reduction of serum PSA in men treated with Polyphenon E compared with controls (-0.87 ng/mL; 95% confidence interval, -1.66 to -0.09).[<a class="bk_pop" href="#CDR0000719335_rl_174_39">39</a>] Although the findings of this U.S. study appear to refute the large effect size suggested by the Italian study [<a class="bk_pop" href="#CDR0000719335_rl_174_39">39</a>,<a class="bk_pop" href="#CDR0000719335_rl_174_41">41</a>,<a class="bk_pop" href="#CDR0000719335_rl_174_42">42</a>] that reported a 90% reduction in prostate cancer among men with HGPIN, overall, the randomized controlled trials have shown a decreased rate of progression to atypical small acinar proliferation or prostate cancer in men with HGPIN treated with GTCs.</p></div><div id="CDR0000719335__206"><h5>Preoperative studies</h5><p id="CDR0000719335__562">Patients scheduled for <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046549/" class="def">radical prostatectomy</a> were randomly assigned to drink green tea, black tea, or a soda five times a day for 5 days. <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044225/" class="def">Bioavailable</a> tea polyphenols were found in prostate samples of the patients who had consumed green tea and black tea. In addition, prostate cancer cells were treated with participants’ serum, and the results showed that there was less proliferation using post-tea serum than using serum obtained before the tea intervention.[<a class="bk_pop" href="#CDR0000719335_rl_174_43">43</a>] In an <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000285990/" class="def">open label</a>, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045831/" class="def">phase II</a> trial, 113 men with prostate cancer were randomly assigned to drink six cups of green tea, black tea, or water before radical prostatectomy.[<a class="bk_pop" href="#CDR0000719335_rl_174_44">44</a>] Ninety-three patients completed the intervention. Although there were no significant differences in markers of proliferation, apoptosis, and oxidation in the prostatectomy tissue, only the men drinking green tea demonstrated small but significant decreases in PSA levels (<i>P</i> = .04).</p><p id="CDR0000719335__563">In an open label, phase II clinical study, prostate cancer patients scheduled for radical prostatectomy consumed four Polyphenon E tablets containing tea polyphenols, providing 800 mg EGCG daily until <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045570/" class="def">surgery</a>. The Polyphenon E treatment had a positive effect on a number of prostate cancer <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045618/" class="def">biomarkers</a>, including PSA, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044222/" class="def">vascular endothelial growth factor (VEGF)</a>, and IGF-1 (a protein associated with increased risk of prostate cancer).[<a class="bk_pop" href="#CDR0000719335_rl_174_45">45</a>]</p><p id="CDR0000719335__564">In a 2011 study, 50 prostate cancer patients were randomly assigned to receive Polyphenon E (800 mg EGCG) or a placebo daily for 3 to 6 weeks before surgery. Treatment with Polyphenon E resulted in greater decreases in serum levels of PSA and IGF-1 than did treatment with placebo, but these differences were not statistically significant. The findings of this study suggest that the chemopreventive effects of green tea polyphenols may be through indirect means and that longer intervention studies may be needed.[<a class="bk_pop" href="#CDR0000719335_rl_174_36">36</a>]</p></div><div id="CDR0000719335__565"><h5>Advanced prostate cancer</h5><p id="CDR0000719335__566">In a small, single-arm study, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000686077/" class="def">hormone-refractory</a> prostate cancer patients received capsules of green tea extract twice daily (375 mg total polyphenols daily; not specified by polyphenol type) for up to 5 months. Although the green tea intervention was well tolerated by most study participants, no patient had a PSA <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044085/" class="def">response</a> (i.e., at least 50% decrease from <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000467830/" class="def">baseline</a>), and all 19 patients were deemed to have <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045850/" class="def">progressive disease</a> within 1 to 5 months.[<a class="bk_pop" href="#CDR0000719335_rl_174_46">46</a>]</p><p id="CDR0000719335__567">In a 2003 study, patients with <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000350224/" class="def">androgen-independent</a>
|
|
<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044058/" class="def">metastatic</a> prostate cancer consumed 6 g of powdered green tea extract daily for up to 4 months. Among 42 participants, 1 patient exhibited a 50% decrease in serum PSA level compared with baseline, but this response was not sustained beyond 2 months. Green tea was well tolerated by most study participants. However, six episodes of grade 3 toxicity occurred, involving <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044043/" class="def">insomnia</a>, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000450096/" class="def">confusion</a>, and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000321374/" class="def">fatigue</a>. These results suggest that in patients with advanced prostate cancer, green tea may have limited benefits.[<a class="bk_pop" href="#CDR0000719335_rl_174_47">47</a>]</p></div></div><div id="CDR0000719335__249"><h4>Current clinical trials</h4><p id="CDR0000719335__250">Check NCI’s list of cancer clinical trials for CAM clinical trials on <a href="https://www.cancer.gov/about-cancer/treatment/clinical-trials/search/results?protocolsearchid=10532603&vers=1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">green tea for prostate cancer</a> and <a href="https://www.cancer.gov/about-cancer/treatment/clinical-trials/search/results?protocolsearchid=10532609&vers=1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">green tea extract for prostate cancer</a> that are actively enrolling patients.</p><p id="CDR0000719335__251">General information about clinical trials is also available from the <a href="https://www.cancer.gov/about-cancer/treatment/clinical-trials" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NCI website</a>.</p></div></div><div id="CDR0000719335__558"><h3>Adverse Effects</h3><p id="CDR0000719335__559">The safety of tea and tea compounds is supported by centuries of consumption by the human population. The bioavailability and tolerance to GTC at doses ranging from 600 to 1,000 mg EGCG at single and multiple doses, and a duration of a few days to 1 year has been well documented in phase I/II clinical trials.[<a class="bk_pop" href="#CDR0000719335_rl_174_33">33</a>-<a class="bk_pop" href="#CDR0000719335_rl_174_37">37</a>,<a class="bk_pop" href="#CDR0000719335_rl_174_40">40</a>,<a class="bk_pop" href="#CDR0000719335_rl_174_43">43</a>-<a class="bk_pop" href="#CDR0000719335_rl_174_47">47</a>] The authors of a phase I trial of oral green tea extract in adult patients with solid tumors reported that a safe dose of green tea extract (1.0 g/m<sup>2</sup>, three times per day) was equivalent to seven to eight Japanese cups (120 mL) of green tea three times per day for 6 months.[<a class="bk_pop" href="#CDR0000719335_rl_174_48">48</a>] The authors concluded that the side effects (neurological and gastrointestinal) of the green tea extract preparation were caffeine related, and not from EGCG. In four phase I, single-dose, and multidose studies that targeted healthy volunteers who took a botanical drug substance containing a mixture of catechins, Polyphenon E, and a dose range of 200 to 1,200 mg EGCG was well tolerated.[<a class="bk_pop" href="#CDR0000719335_rl_174_29">29</a>,<a class="bk_pop" href="#CDR0000719335_rl_174_30">30</a>,<a class="bk_pop" href="#CDR0000719335_rl_174_37">37</a>-<a class="bk_pop" href="#CDR0000719335_rl_174_39">39</a>,<a class="bk_pop" href="#CDR0000719335_rl_174_41">41</a>,<a class="bk_pop" href="#CDR0000719335_rl_174_42">42</a>] Adverse effects with a possible relationship to the study drug reported in these studies have been grade 2 to 3 and included <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044787/" class="def">asthenia</a>, headache, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046684/" class="def">abdominal</a> pain, chest pain, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000306496/" class="def">diarrhea</a>, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044200/" class="def">dyspepsia</a>, eructation, flatulence, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000390302/" class="def">nausea</a>, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000390324/" class="def">vomiting</a>, dizziness, vasodilation, and rash. These studies have demonstrated that although increased oral bioavailability occurs when GTCs are consumed in a fasting state, increased gastrointestinal toxicity is also more common. Gastrointestinal adverse effects were usually mild and seen most often at the higher dose levels. Onset of gastrointestinal events typically occurred within 2 to 3 hours of dosing and resolved within 2 hours. No grade 3 or higher events were reported with a possible relationship to the study drug.[<a class="bk_pop" href="#CDR0000719335_rl_174_45">45</a>]</p><p id="CDR0000719335__600">Green tea has been well tolerated in clinical studies of men with prostate cancer.[<a class="bk_pop" href="#CDR0000719335_rl_174_40">40</a>,<a class="bk_pop" href="#CDR0000719335_rl_174_45">45</a>] In a 2005 study, the most commonly reported side effects were gastrointestinal symptoms. These symptoms were mild for all but two men, who experienced severe <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044103/" class="def">anorexia</a> and moderate <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046183/" class="def">dyspnea</a>.[<a class="bk_pop" href="#CDR0000719335_rl_174_46">46</a>] With the duration of intervention in these studies ranging from single, one-time administration to a maximum of 90 days, the safety data from these studies are limited to short-term safety of EGCG and GTCs.</p><p id="CDR0000719335__598">Data from clinical trials [<a class="bk_pop" href="#CDR0000719335_rl_174_39">39</a>,<a class="bk_pop" href="#CDR0000719335_rl_174_41">41</a>] report long-term safety of EGCG containing GTCs, for use in men with precursor lesions of prostate cancer for prevention of prostate cancer. One study [<a class="bk_pop" href="#CDR0000719335_rl_174_41">41</a>] administered approximately 300 mg EGCG per day for 1 year without any reported toxicities. </p><p id="CDR0000719335__599">In the recently completed U.S. trial, 400 mg of EGCG containing Polyphenon E was administered for 1 year to nonfasting men with HGPIN and atypical small acinar proliferation. More possible and probable grade 2 through grade 3 events in men who received Polyphenon E were observed and compared with those in men who received placebo. Only one man who received Polyphenon E reported grade 3 nausea, which was determined to possibly be related to the study agent.[<a class="bk_pop" href="#CDR0000719335_rl_174_39">39</a>]</p><p id="CDR0000719335__560">In recent years, oral consumption of varying doses and compositions of green tea extracts (GTEs) has been associated with several instances of hepatotoxicity.[<a class="bk_pop" href="#CDR0000719335_rl_174_23">23</a>,<a class="bk_pop" href="#CDR0000719335_rl_174_35">35</a>,<a class="bk_pop" href="#CDR0000719335_rl_174_49">49</a>-<a class="bk_pop" href="#CDR0000719335_rl_174_51">51</a>] Most affected patients were women, and many were consuming GTEs for the purpose of weight loss. Although hepatotoxicity in most cases resolved within 4 months of stopping GTEs, there have been cases of positive rechallenge and liver failure requiring liver transplantation. One report described a case of acute liver failure that required transplantation in a woman who consumed GTE capsules.[<a class="bk_pop" href="#CDR0000719335_rl_174_50">50</a>] The capsules contained Polyphenon 70A (a concentrated, enriched, and pasteurized hot-water extract of green tea) and 120 mg GTE. Because no other causal relationship could be identified, the treating physicians concluded that the fulminant liver failure experienced by this patient was most likely related to the consumption of over-the-counter GTE weight-loss supplements. In addition, the sale of an ethanolic GTE sold as a weight-reduction aid was suspended in 2003 after reports associated hepatotoxicity (four cases in Spain and nine cases in France) with its use.[<a class="bk_pop" href="#CDR0000719335_rl_174_51">51</a>] Time to onset of hepatotoxicity following ingestion of GTEs ranged from several days to several months. Increased oral bioavailability occurs when GTEs are administered on an empty stomach after an overnight fast. Increased toxicity, including hepatotoxicity, is observed when Polyphenon E or EGCG is administered to fasted dogs.[<a class="bk_pop" href="#CDR0000719335_rl_174_23">23</a>] The U.S. Food and Drug Administration's Division of Drug Oncology Products has recommended that Polyphenon E be taken with food by subjects participating in clinical studies. In addition, liver function tests should be considered while individuals are on treatment.</p></div><div id="CDR0000719335_rl_174"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000719335_rl_174_1">Landau JM, Lambert JD, Yang CS: Green tea. In: Heber D, Blackburn GL, Go VLW, et al., eds.: Nutritional Oncology. 2nd ed. Burlington, Ma: Academic Press, 2006, pp 597-606.</div></li><li><div class="bk_ref" id="CDR0000719335_rl_174_2">Yang CS, Wang H: Mechanistic issues concerning cancer prevention by tea catechins. 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[<a href="https://pubmed.ncbi.nlm.nih.gov/16424063" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16424063</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_174_42">Brausi M, Rizzi F, Bettuzzi S: Chemoprevention of human prostate cancer by green tea catechins: two years later. A follow-up update. Eur Urol 54 (2): 472-3, 2008. [<a href="https://pubmed.ncbi.nlm.nih.gov/18406041" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18406041</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_174_43">Henning SM, Aronson W, Niu Y, et al.: Tea polyphenols and theaflavins are present in prostate tissue of humans and mice after green and black tea consumption. J Nutr 136 (7): 1839-43, 2006. [<a href="https://pubmed.ncbi.nlm.nih.gov/16772446" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16772446</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_174_44">Henning SM, Wang P, Said JW, et al.: Randomized clinical trial of brewed green and black tea in men with prostate cancer prior to prostatectomy. Prostate 75 (5): 550-9, 2015. [<a href="/pmc/articles/PMC4334734/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4334734</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/25545744" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25545744</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_174_45">McLarty J, Bigelow RL, Smith M, et al.: Tea polyphenols decrease serum levels of prostate-specific antigen, hepatocyte growth factor, and vascular endothelial growth factor in prostate cancer patients and inhibit production of hepatocyte growth factor and vascular endothelial growth factor in vitro. Cancer Prev Res (Phila) 2 (7): 673-82, 2009. [<a href="https://pubmed.ncbi.nlm.nih.gov/19542190" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19542190</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_174_46">Choan E, Segal R, Jonker D, et al.: A prospective clinical trial of green tea for hormone refractory prostate cancer: an evaluation of the complementary/alternative therapy approach. Urol Oncol 23 (2): 108-13, 2005 Mar-Apr. [<a href="https://pubmed.ncbi.nlm.nih.gov/15869995" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15869995</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_174_47">Jatoi A, Ellison N, Burch PA, et al.: A phase II trial of green tea in the treatment of patients with androgen independent metastatic prostate carcinoma. Cancer 97 (6): 1442-6, 2003. [<a href="https://pubmed.ncbi.nlm.nih.gov/12627508" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12627508</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_174_48">Pisters KM, Newman RA, Coldman B, et al.: Phase I trial of oral green tea extract in adult patients with solid tumors. J Clin Oncol 19 (6): 1830-8, 2001. [<a href="https://pubmed.ncbi.nlm.nih.gov/11251015" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11251015</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_174_49">Bonkovsky HL: Hepatotoxicity associated with supplements containing Chinese green tea (Camellia sinensis). Ann Intern Med 144 (1): 68-71, 2006. [<a href="https://pubmed.ncbi.nlm.nih.gov/16389263" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16389263</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_174_50">Molinari M, Watt KD, Kruszyna T, et al.: Acute liver failure induced by green tea extracts: case report and review of the literature. Liver Transpl 12 (12): 1892-5, 2006. [<a href="https://pubmed.ncbi.nlm.nih.gov/17133573" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17133573</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_174_51">Pedrós C, Cereza G, García N, et al.: [Liver toxicity of Camellia sinensis dried etanolic extract]. Med Clin (Barc) 121 (15): 598-9, 2003. [<a href="https://pubmed.ncbi.nlm.nih.gov/14622530" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 14622530</span></a>]</div></li></ol></div></div><div id="CDR0000719335__16"><h2 id="_CDR0000719335__16_">Lycopene</h2><div id="CDR0000719335__1"><h3>Overview</h3><p id="CDR0000719335__2">This section contains the following key information:</p><ul id="CDR0000719335__3"><li class="half_rhythm"><div><a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044909/" class="def">Lycopene</a> is a <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046132/" class="def">carotenoid</a>, a natural <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046225/" class="def">pigment</a> made by plants and various fruits and vegetables, including tomatoes, apricots, guavas, and watermelon.</div></li><li class="half_rhythm"><div>Lycopene's <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000463702/" class="def">absorption</a> is improved with concurrent dietary fat intake.</div></li><li class="half_rhythm"><div>Lycopene inhibits <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045592/" class="def">androgen</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044958/" class="def">receptor</a> expression in <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000445079/" class="def">prostate cancer</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046476/" class="def">cells</a>
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<i><a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045733/" class="def">in vitro</a></i> and, along with some of its <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000462687/" class="def">metabolites</a>, reduces prostate cancer <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046479/" class="def">cell proliferation</a> and may <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000390300/" class="def">modulate</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000597111/" class="def">cell-cycle</a> progression.</div></li><li class="half_rhythm"><div>Lycopene may also affect the <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000653119/" class="def">insulin-like growth factor</a> (IGF) <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044047/" class="def">intracellular</a> pathway in prostate cancer cells.</div></li><li class="half_rhythm"><div>Results from several <i>in vitro</i> and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000454774/" class="def">animal studies</a> have indicated that lycopene may have <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045487/" class="def">chemopreventive</a> effects for cancers of the prostate, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000445084/" class="def">skin</a>, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000444971/" class="def">breast</a>, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000445043/" class="def">lung</a>, and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044242/" class="def">liver</a>; however, human trials have been inconsistent in their findings. </div></li><li class="half_rhythm"><div><a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045961/" class="def">Clinical trials</a> utilizing lycopene in prostate cancer patients with various different clinical presentations (e.g., early stage, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046540/" class="def">prostate-specific antigen</a> (PSA) <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045866/" class="def">relapse</a>, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000478743/" class="def">advanced disease</a>) have yielded inconsistent results.</div></li><li class="half_rhythm"><div>The <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000454785/" class="def">U.S. Food and Drug Administration</a> (FDA) has accepted the determination by various companies that their lycopene-containing products meet the FDA’s requirements for the designation of Generally Recognized as Safe (GRAS). In clinical trials involving prostate cancer patients, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044664/" class="def">doses</a> ranging from 10 to 120 mg/d have been well tolerated, with only occasional mild-to-moderate <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045692/" class="def">gastrointestinal</a> toxicities.</div></li></ul></div><div id="CDR0000719335__4"><h3>General Information and History</h3><p id="CDR0000719335__5">Lycopene is a <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044709/" class="def">phytochemical</a> that belongs to a group of pigments known as carotenoids. It is red and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000373086/" class="def">lipophilic</a>. As a natural pigment made by plants, lycopene helps to protect plants from light-induced stress,[<a class="bk_pop" href="#CDR0000719335_rl_16_1">1</a>] and it also transfers light energy during <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000729737/" class="def">photosynthesis</a>.[<a class="bk_pop" href="#CDR0000719335_rl_16_2">2</a>] Lycopene is found in a number of fruits and vegetables, including apricots, guavas, and watermelon, but the majority of lycopene consumed in the United States is from tomato-based products.[<a class="bk_pop" href="#CDR0000719335_rl_16_1">1</a>] </p><p id="CDR0000719335__622">Lycopene has been investigated for its role in <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045641/" class="def">chronic</a> diseases, including <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044005/" class="def">cardiovascular</a> disease and cancer. Numerous <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000257225/" class="def">epidemiological</a> studies suggest that lycopene may help prevent cardiovascular disease. Lycopene may protect against cardiovascular disease by decreasing <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000407756/" class="def">cholesterol</a> synthesis and increasing the degradation of low-density lipoproteins,[<a class="bk_pop" href="#CDR0000719335_rl_16_3">3</a>] although some interventional studies have shown mixed results.[<a class="bk_pop" href="#CDR0000719335_rl_16_4">4</a>]</p><p id="CDR0000719335__623"> A number of <i>in vitro</i> and <i><a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046352/" class="def">in vivo</a></i> studies suggest that lycopene may also be protective against cancers of the skin, breast, lung, and liver.[<a class="bk_pop" href="#CDR0000719335_rl_16_5">5</a>] However, epidemiological studies have yielded inconsistent findings regarding lycopene's potential in reducing cancer risk. </p><p id="CDR0000719335__624">The few human <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000454757/" class="def">intervention</a> trials have been small and generally focused on intermediate <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000346519/" class="def">endpoints</a> and not response of clinically evident disease or overall survival and thus have limited translation to practice.[<a class="bk_pop" href="#CDR0000719335_rl_16_2">2</a>,<a class="bk_pop" href="#CDR0000719335_rl_16_6">6</a>]</p><p id="CDR0000719335__8">On the basis of overall evidence, the association between tomato consumption and reduced risk of prostate cancer is limited.[<a class="bk_pop" href="#CDR0000719335_rl_16_7">7</a>]</p></div><div id="CDR0000719335__9"><h3>Preclinical/Animal Studies</h3><div id="CDR0000719335__17"><h4><i>In vitro</i> studies</h4><p id="CDR0000719335__18"><i>In vitro</i> studies that have examined a link between lycopene and prostate <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046487/" class="def">carcinogenesis</a> have suggested several mechanisms by which lycopene might reduce prostate cancer risk. Lycopene is broken down into a number of metabolites that are thought to have various <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044510/" class="def">biological</a> effects, including <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000043997/" class="def">antioxidant</a> capabilities and a role in gap-junction communication.[<a class="bk_pop" href="#CDR0000719335_rl_16_8">8</a>] </p><p id="CDR0000719335__19">Treating normal human prostate <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045682/" class="def">epithelial</a> cells with lycopene resulted in <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044110/" class="def">dose-dependent</a> growth inhibition, indicating that inhibition of prostate cell proliferation may be one way lycopene may lower the risk of prostate cancer.[<a class="bk_pop" href="#CDR0000719335_rl_16_9">9</a>]</p><p id="CDR0000719335__20">In addition, treating prostate cancer cells with lycopene resulted in a significant decrease in the number of lycopene-treated cells in the S phase of the <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000597111/" class="def">cell cycle</a>, suggesting that lycopene may lower cell proliferation by altering cell-cycle progression. Moreover, apo-12’-lycopenal, a lycopene metabolite, reduced prostate cancer cell proliferation and may modulate cell-cycle progression.[<a class="bk_pop" href="#CDR0000719335_rl_16_10">10</a>]</p><p id="CDR0000719335__21">Some studies have suggested that cancer cells have altered cholesterol-biosynthesis pathways. Treating prostate cancer cells with lycopene resulted in dose-dependent decreases in 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase (the rate-limiting <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046081/" class="def">enzyme</a> in cholesterol synthesis), total cholesterol, and cell growth, and an increase in <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046524/" class="def">apoptosis</a>. However, adding <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000729751/" class="def">mevalonate</a> prevented the growth-inhibitory effects of lycopene, indicating that the mevalonate pathway may be important to the anticancer activity of lycopene.[<a class="bk_pop" href="#CDR0000719335_rl_16_11">11</a>] Lycopene may also affect cholesterol levels in prostate cancer cells by activating the <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000729755/" class="def">peroxisome proliferator-activated receptor gamma</a> (PPARγ)-<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000729764/" class="def">liver X receptor alpha</a> (LXRα)-ATP-binding cassette, subfamily 1 <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000729767/" class="def">(ABCA1) pathway</a>, which leads to decreased cholesterol levels and may ultimately result in decreased cell proliferation. ABCA1 mediates cholesterol efflux, and PPARγ has been shown to inhibit the growth and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046445/" class="def">differentiation</a> of prostate cancer cells. In one study, treating prostate cancer cells with lycopene resulted in increased expression of PPARγ, LXRα, and ABCA1 as well as lower total cholesterol. In addition, when the cells were treated with a PPARγ <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000350250/" class="def">antagonist</a>, cell proliferation increased, whereas treating cells with a combination of the PPARγ antagonist and lycopene decreased cell proliferation.[<a class="bk_pop" href="#CDR0000719335_rl_16_12">12</a>]</p><p id="CDR0000719335__22">Adding lycopene to medium containing the LNCaP human prostate <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046216/" class="def">adenocarcinoma</a> cell line resulted in decreased <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000045671/" class="def">DNA</a> synthesis and inhibition of androgen-receptor gene-element activity and expression.[<a class="bk_pop" href="#CDR0000719335_rl_16_13">13</a>] In a study that examined the <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045837/" class="def">physiologically</a> relevant <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000683342/" class="def">concentration</a> of lycopene (2 mmol/L) or <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046688/" class="def">placebo</a> for 48 hours on <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000557359/" class="def">protein expression</a> in human primary prostatic epithelial cells, proteins that were significantly upregulated or downregulated following lycopene exposure were those proteins involved in antioxidant responses, cytoprotection, apoptosis, growth inhibition, androgen receptor signaling, and the <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000653105/" class="def">AKT</a>/<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000653126/" class="def">mTOR</a> cascade. These data are consistent with previous studies, suggesting that lycopene can prevent <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045772/" class="def">malignant</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046628/" class="def">transformation</a> in human prostatic epithelial cells at the stages of cancer initiation, promotion, and/or progression.[<a class="bk_pop" href="#CDR0000719335_rl_16_14">14</a>]</p><p id="CDR0000719335__625">A study examining the effect of lycopene on multiple points along the <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000773861/" class="def">nuclear factor-kappa B</a> (NF-kappa B) signaling pathways in prostate <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000695994/" class="def">cell lines</a> demonstrated a 30% to 40% reduction in inhibitor of kappa B (I-kappa B) <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000641137/" class="def">phosphorylation</a>, NF-kappa B <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000390290/" class="def">transcriptional</a> activity and a significant reduction in cell growth at the physiologically relevant concentration of 1.25 μM or higher.[<a class="bk_pop" href="#CDR0000719335_rl_16_15">15</a>] These results provided evidence that the anticancer properties of lycopene may occur through inhibition of the NF-kappa B signaling pathway, beginning at the early stage of <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044586/" class="def">cytoplasmic</a> IKK kinase activity, which then leads to reduced NF-kappa B–responsive gene regulation. Additionally, these effects in the cancer cells were observed at concentrations of lycopene that are relevant and achievable <i>in vivo</i>.</p><p id="CDR0000719335__23">Some studies have assessed possible beneficial interactions between lycopene and conventional cancer therapies. In one such study, various types of prostate cancer cells were treated with a combination of lycopene and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045382/" class="def">docetaxel</a>, a drug used to treat patients with <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045636/" class="def">castration</a>-resistant prostate cancer, or each drug alone. The combination treatment inhibited proliferation in four of five cell lines to a greater extent than did treatment with docetaxel alone. The findings suggest that the mechanism for these effects may involve the IGF-1 receptor (IGF-1R) pathway.[<a class="bk_pop" href="#CDR0000719335_rl_16_16">16</a>]</p></div><div id="CDR0000719335__24"><h4>Animal studies</h4><p id="CDR0000719335__25">In a <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044652/" class="def">chemoprevention study</a>, 59 <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000691466/" class="def">transgenic</a> adenocarcinoma of the mouse prostate (TRAMP) mice were fed diets supplemented with tomato paste or lycopene beadlets (both preparations contained 28 mg lycopene/kg chow). Mice that received lycopene beadlets exhibited a larger reduction in prostate cancer incidence compared with control mice than mice supplemented with tomato paste, suggesting that lycopene beadlets may provide greater chemopreventive effects than tomato paste.[<a class="bk_pop" href="#CDR0000719335_rl_16_17">17</a>]</p><p id="CDR0000719335__26">Ketosamines are <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000285960/" class="def">carbohydrate</a> derivatives formed when food is dehydrated. In one study, FruHis (a ketosamine in dehydrated tomatoes) combined with lycopene resulted in greater growth inhibition of implanted rat prostate cancer cells than did lycopene or FruHis alone. In addition, in a N-methyl-N-nitrosourea/testosterone-induced prostate carcinogenesis model, rats fed a tomato paste and FruHis diet had longer survival times than rats fed only with tomato paste or tomato powder.[<a class="bk_pop" href="#CDR0000719335_rl_16_18">18</a>]</p><p id="CDR0000719335__28">Lycopene has also been studied for potential therapeutic effects in <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044095/" class="def">xenograft</a> models. In one study, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044579/" class="def">athymic nude mice</a> were <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044678/" class="def">injected</a> with human <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000350224/" class="def">androgen-independent</a> prostate cancer cells and were treated with either lycopene (4 mg/kg body weight or 16 mg/kg body weight) or <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045328/" class="def">beta-carotene</a> (16 mg/kg body weight). Supplementing mice with lycopene or beta-carotene resulted in decreased <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046634/" class="def">tumor</a> growth.[<a class="bk_pop" href="#CDR0000719335_rl_16_19">19</a>] In an <i>in vitro</i> study, the investigators demonstrated the effect of lycopene in androgen-independent prostate cancer cell lines.[<a class="bk_pop" href="#CDR0000719335_rl_16_20">20</a>] In another study, nude mice were injected with human prostate cancer cells and treated with <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046339/" class="def">intraperitoneal</a> injections of docetaxel, lycopene (15 mg/kg per day) administered via <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000729771/" class="def">gavage</a>, or a combination of both. Mice exhibited longer survival times and smaller tumors when treated with a combination of docetaxel and lycopene than when they were treated with docetaxel alone.[<a class="bk_pop" href="#CDR0000719335_rl_16_16">16</a>]</p></div></div><div id="CDR0000719335__12"><h3>Human Studies</h3><div id="CDR0000719335__30"><h4>Epidemiologic studies</h4><p id="CDR0000719335__31">Several epidemiologic studies have assessed potential associations between lycopene intake and prostate cancer incidence.</p><p id="CDR0000719335__32">Epidemiological studies have demonstrated that populations with high intake of dietary lycopene have lower risk of prostate cancer.[<a class="bk_pop" href="#CDR0000719335_rl_16_7">7</a>,<a class="bk_pop" href="#CDR0000719335_rl_16_9">9</a>-<a class="bk_pop" href="#CDR0000719335_rl_16_13">13</a>] Prospective and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000348989/" class="def">case-control studies</a> have shown lycopene to be significantly lower in the serum and tissue of patients with cancer than in controls,[<a class="bk_pop" href="#CDR0000719335_rl_16_7">7</a>,<a class="bk_pop" href="#CDR0000719335_rl_16_16">16</a>-<a class="bk_pop" href="#CDR0000719335_rl_16_19">19</a>,<a class="bk_pop" href="#CDR0000719335_rl_16_21">21</a>] while other studies have failed to demonstrate such a connection.[<a class="bk_pop" href="#CDR0000719335_rl_16_22">22</a>]</p><p id="CDR0000719335__33">An association between lycopene serum concentration and risk of cancer was also examined in men participating in the Kuopio Ischaemic Heart Disease Risk Factor study in Finland. In this <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000286693/" class="def">prospective cohort study</a>, an inverse association between lycopene levels and overall cancer risk was observed, suggesting that higher concentrations of lycopene may help lower cancer risk overall. Men with the highest levels of serum lycopene had a 45% lower risk of cancer than did men with the lowest levels of lycopene (risk ratio, 0.55; 95% confidence interval (CI), 0.34–0.89; <i>P</i> = .015). However, when the analysis was restricted to specific cancer types, an association was observed for other cancers (risk ratio, 0.43; 95% CI, 0.23–0.79; <i>P</i> = .007) but not prostate cancer.[<a class="bk_pop" href="#CDR0000719335_rl_16_23">23</a>]</p><p id="CDR0000719335__34">A 2004 <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000691484/" class="def">meta-analysis</a> of studies investigating tomato intake and prostate cancer risk found a small positive effect of tomato products on risk reduction. Among men who consumed high amounts of raw tomato products, the relative risk (RR) of prostate cancer was 0.89 (95% CI, 0.80–1.00), compared with men who ate the least amount of raw tomatoes. For men who consumed the most cooked tomato products, the RR was 0.81 (95% CI, 0.71–0.92).[<a class="bk_pop" href="#CDR0000719335_rl_16_24">24</a>] A 2013 meta-analysis, including four of five cohort studies from the 2004 meta-analysis, two new meta-analyses, and three case-control studies from the previous study plus eight new ones, reported less-convincing evidence for risk reduction.[<a class="bk_pop" href="#CDR0000719335_rl_16_25">25</a>] Among men who consumed high amounts of raw tomato products, the RR of prostate cancer was 0.81 (95% CI, 0.59–1.10), compared with men who ate the least amount of raw tomatoes. For men who consumed the most cooked tomato products, the RR was 0.85 (95% CI, 0.69–1.06). The authors concluded that tomatoes may play a modest role in the <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000439419/" class="def">prevention</a> of prostate cancer.</p><p id="CDR0000719335__35">The National Cancer Institute's Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial is an ongoing, prospective study that has been a source of subjects for investigations of an association between lycopene intake and prostate cancer risk. A 2006 study examined lycopene and tomato product intakes and prostate cancer risk among PLCO participants who had been followed for an average of 4.2 years. Lycopene and tomato product intakes were assessed via food frequency questionnaires. Overall, no association was found between dietary intake of lycopene or tomato products and the risk of prostate cancer. However, among men with a <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000302456/" class="def">family history</a> of prostate cancer, increased lycopene consumption was associated with decreased prostate cancer risk.[<a class="bk_pop" href="#CDR0000719335_rl_16_26">26</a>] A <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044671/" class="def">follow-up</a> study was conducted that examined serum lycopene and risk of prostate cancer in the same group of PLCO participants. The results suggest that there was no significant difference in serum lycopene concentrations between healthy participants and participants who developed prostate cancer.[<a class="bk_pop" href="#CDR0000719335_rl_16_27">27</a>]</p><p id="CDR0000719335__461">The Health Professionals Follow-up Study obtained dietary information and ascertained total and lethal prostate cancer cases from 1986 through January 31, 2010. Higher lycopene intake was inversely associated with total prostate cancer risk (hazard ratio [HR], 0.91; 95% CI, 0.84–1.00) and lethal prostate cancer risk (HR, 0.72; 95% CI, 0.56–0.94). A subset analysis was restricted to men who had at least one negative PSA test at the onset, to reduce the influence of PSA screening on the association. The inverse association became markedly stronger (HR, 0.47; 95% CI, 0.29–0.75 for lethal prostate cancer). Levels of <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046636/" class="def">tumor markers</a> for <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046529/" class="def">angiogenesis</a>, apoptosis, and cellular proliferation and differentiation were <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000454803/" class="def">monitored</a>. Three of the tumor angiogenesis markers were strongly associated with lycopene intake, so that men with higher intake had tumors that demonstrated less angiogenic potential.[<a class="bk_pop" href="#CDR0000719335_rl_16_28">28</a>]</p><p id="CDR0000719335__626">At least two studies examined the effect of lycopene blood levels on the risk of <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000386205/" class="def">high-grade</a> prostate cancer. The first study examined the associations between carotenoid levels and the risk of high-grade prostate cancer, and also considered antioxidant-related genes and tumor instability. This study demonstrated that <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045839/" class="def">plasma</a> carotenoids at diagnosis, particularly among men carrying specific somatic variations, were inversely associated with risk of high-grade prostate cancer. Higher lycopene concentrations were associated with less genomic instability among men with <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000386213/" class="def">low-grade</a> disease, indicating that lycopene may inhibit progression of prostate cancer early in its natural history.[<a class="bk_pop" href="#CDR0000719335_rl_16_29">29</a>]</p><p id="CDR0000719335__627">In another study examining whether carotenoid intake and adipose tissue carotenoid levels were inversely associated with prostate cancer aggressiveness, results suggested that diets high in lycopene may protect against <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046053/" class="def">aggressive</a> prostate cancer in white Americans and diets high in beta-cryptoxanthin may protect against aggressive prostate cancer in African Americans.[<a class="bk_pop" href="#CDR0000719335_rl_16_30">30</a>]</p><p id="CDR0000719335__649"> One study investigated the correlation between lycopene blood levels and the rate of progression of prostate cancer. This study examined plasma carotenoids and tocopherols in relation to PSA levels among men with <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000543628/" class="def">biochemical recurrence</a> of prostate cancer. This study indicated that the plasma <i>cis</i>-lutein/zeaxanthin level at 3 months was inversely related to PSA level at 3 months (<i>P</i> = .0008), while <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000691423/" class="def">alpha-tocopherol</a> (<i>P</i> = .01), beta-cryptoxanthin (<i>P</i> = .01), and all-trans-lycopene (<i>P</i> = .004) levels at 3 months were inversely related to PSA levels at 6 months. Percentage increase in alpha-tocopherol and trans-beta-carotene levels from baseline to month 3 was associated with lower PSA levels at 3 and 6 months. Percentage increase in beta-cryptoxanthin, cis-lutein/zeaxanthin and all-trans-lycopene was associated with lower PSA levels at 6 months only.[<a class="bk_pop" href="#CDR0000719335_rl_16_31">31</a>]</p><p id="CDR0000719335__650">A study examined the association of prediagnosis and postdiagnosis dietary lycopene and tomato product intake with prostate-cancer specific <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000496502/" class="def">mortality</a> in a prospective cohort of men diagnosed with <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045805/" class="def">nonmetastatic</a> prostate cancer. No association between serum lycopene, tomato products, and prostate-cancer specific mortality was observed. Among men with high-risk cancers (T3–T4, Gleason score 8–10, or nodal involvement), consistently reporting lycopene intake that was at or above the median was associated with lower prostate-cancer specific mortality.[<a class="bk_pop" href="#CDR0000719335_rl_16_32">32</a>]</p><p id="CDR0000719335__266">The variability in these epidemiological study results may be related to lycopene source; exposure misclassification; inconsistent measures of intake; differences in absorption; differences in individual lycopene metabolism; lack of a dose response; and confounding lifestyle factors, such as obesity, use of tobacco and alcohol, other dietary differences, varying standardization of quantities and compositions of lycopene, geographical location, and genetic risk factors. Most studies have examined the association of lycopene intake with the risk of all prostate cancers and have not separately considered indolent versus aggressive disease. Given these caveats, results based on epidemiological evidence should be interpreted with caution.</p></div><div id="CDR0000719335__36"><h4>Intervention studies</h4><p id="CDR0000719335__37">A number of clinical studies have been conducted investigating lycopene as a chemopreventive agent and as a potential treatment for prostate cancer. </p><div id="CDR0000719335__662"><h5>Bioavailability</h5><p id="CDR0000719335__663">The bioavailability of lycopene has been examined and demonstrated in several studies relating lycopene to prostate cancer and other diseases. The <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044225/" class="def">bioavailability</a> of lycopene is greater in processed tomato products, such as tomato paste and tomato puree, than in raw tomatoes.[<a class="bk_pop" href="#CDR0000719335_rl_16_4">4</a>] Lycopene bioavailability has been observed to be highly variable, which may lead to varying biological effects after lycopene consumption. It is postulated that these variations, at least in part, can be attributed to several <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000458046/" class="def">single nucleotide polymorphisms</a> in genes involved in red-pigment lycopene and lipid metabolism. In a study to define the impact of typical servings of commercially available tomato products on resultant plasma and prostate lycopene concentrations,[<a class="bk_pop" href="#CDR0000719335_rl_16_33">33</a>] men scheduled to undergo prostatectomy (n = 33) were randomly assigned to either a lycopene-restricted control group (<5 mg/d) or a tomato soup (2–2¾ cups/d prepared), tomato sauce (142–198 g/d or 5–7 oz/d), or vegetable juice (325–488 mL/d or 11–16.5 fluid oz/d) intervention providing 25 to 35 mg of lycopene per day. The end-of-study prostate lycopene concentration was 0.16 nmol/g (standard error of the mean, 0.02) in the controls, but was 3.5-, 3.6- and 2.2-fold higher in tomato soup (<i>P</i> = .001), sauce (<i>P</i> = .001), and juice (<i>P</i> = .165) consumers, respectively. Prostate lycopene concentration was moderately correlated with postintervention plasma lycopene concentrations (correlation coefficient, 0.60; <i>P</i> = .001), indicating that additional factors have an impact on tissue concentrations. While the primary geometric lycopene isomer in tomato products was all-trans (80%–90%), plasma and prostate isomers were 47% and 80% <i>cis</i>-lycopene, respectively, demonstrating a shift towards cis accumulation. Consumption of typical servings of processed tomato products results in differing plasma and prostate lycopene concentrations. Factors including meal composition and genetics deserve further evaluation to determine their impacts on lycopene absorption, isomerization, and biodistribution.[<a class="bk_pop" href="#CDR0000719335_rl_16_34">34</a>]</p><p id="CDR0000719335__664">There is evidence that dietary fat may help increase the absorption of carotenoids, including lycopene. In one experiment, healthy volunteers consumed mixed-vegetable salads with nonfat, low-fat, or full-fat salad dressing. Analysis of blood samples indicated that eating full-fat salad dressing led to more carotenoid absorption than eating low-fat or nonfat dressing.[<a class="bk_pop" href="#CDR0000719335_rl_16_35">35</a>] Results of a <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045858/" class="def">randomized</a> study published in 2005 demonstrated that cooking diced tomatoes with olive oil significantly increased lycopene absorption compared with cooking tomatoes without olive oil.[<a class="bk_pop" href="#CDR0000719335_rl_16_36">36</a>] In another study,[<a class="bk_pop" href="#CDR0000719335_rl_16_37">37</a>] there was no difference in <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045839/" class="def">plasma</a> lycopene levels following consumption of tomatoes mixed with olive oil or tomatoes mixed with sunflower oil, suggesting that absorption of lycopene may not be dependent on the type of oil used. However, this study found that combining olive oil, but not sunflower oil, with tomatoes resulted in greater plasma antioxidant activity.</p></div><div id="CDR0000719335__651"><h5>Pharmacodynamic Studies</h5><p id="CDR0000719335__652">Healthy males participated in a crossover design study that attempted to differentiate the effects of a tomato matrix from those of lycopene by using lycopene-rich red tomatoes, lycopene-free yellow tomatoes, and purified lycopene. Thirty healthy men aged 50 to 70 years were randomly assigned to two groups with each group consuming 200 g/d of yellow tomato paste (lycopene, 0 mg) and 200 g/d of red tomato paste (lycopene, 16 mg) as part of their regular diet for 1 week, separated by a 2-week washout period. Then, in a parallel design, the first group underwent supplementation with purified lycopene (16 mg/d) for 1 week, whereas the second group received a placebo. Sera samples collected before and after the interventions were incubated with lymph node cancer prostate cells to measure the expression of 45 target genes. In this placebo-controlled trial, circulating lycopene concentration increased only after consumption of red tomato paste and purified lycopene. Lipid profile, antioxidant status, PSA, and IGF-1 were not modified by consumption of tomato pastes and lycopene. When prostate cancer cells were treated <i>in vitro</i> with sera collected from men after red tomato paste consumption, IGF binding protein-3 (IGFBP-3) and the ratio of Bax to Bcl2 were up regulated, and cyclin-D1, p53, and Nrf-2 were down regulated compared with expression levels obtained using sera taken after the first washout period. Intermediate gene expression changes were observed using sera collected from participants after consumption of yellow tomato paste with low carotenoid content. Cell incubation with sera from men who consumed purified lycopene led to significant up-regulation of IGFBP-3, c-fos, and uPAR compared with sera collected after placebo consumption. These findings suggest that lycopene may not be the only factor responsible for the cancer-protective effects of tomatoes.[<a class="bk_pop" href="#CDR0000719335_rl_16_38">38</a>]</p></div><div id="CDR0000719335__653"><h5>Prevention/Early Treatment </h5><p id="CDR0000719335__654">In another study, the effect of tomato sauce on apoptosis in <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046509/" class="def">benign prostatic hyperplasia</a> (BPH) tissue and carcinomas was examined. Patients who were scheduled for <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045851/" class="def">prostatectomy</a> were given tomato sauce pasta entrees (30 mg/day of lycopene) to eat daily for 3 weeks before <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045570/" class="def">surgery</a>. Patients scheduled for surgery who did not receive the tomato sauce pasta entrees served as <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044149/" class="def">control subjects</a>. Those who consumed the tomato sauce pasta entrees exhibited significantly decreased serum PSA levels and increased apoptotic cell death in BPH tissue and carcinomas.[<a class="bk_pop" href="#CDR0000719335_rl_16_39">39</a>]</p><p id="CDR0000719335__655">One study of 40 patients with high-grade <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044345/" class="def">prostate intraepithelial neoplasia</a> (HGPIN) received 4 mg of lycopene twice a day or no lycopene supplementation for 2 years. A greater decrease in serum PSA levels was observed in men treated with lycopene supplements, compared with those who did not take the supplementation. During follow-up, adenocarcinomas were diagnosed more often in patients who had not received the supplements (6 of 20) than in men who had received lycopene (2 of 20). These findings suggest that lycopene may be effective in preventing HGPIN from progressing to prostate cancer.[<a class="bk_pop" href="#CDR0000719335_rl_16_40">40</a>] In another study, men at high risk of prostate cancer (e.g., HGPIN) were randomly assigned to receive a daily multivitamin (that did not contain lycopene) or the same multivitamin and a lycopene supplement (30 mg/day) for 4 months. No <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044167/" class="def">statistically-significant</a> difference was observed in serum PSA levels between the two treatment groups. [<a class="bk_pop" href="#CDR0000719335_rl_16_41">41</a>] Another <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045858/" class="def">randomized</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044840/" class="def">placebo-controlled</a> study of consumption of a lycopene-rich tomato extract that was taken for approximately 6 months in 58 men with HGPIN reported no discernible effect on cell proliferation or <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000491156/" class="def">cell cycle inhibition</a> in <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045614/" class="def">benign</a> prostatic <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046423/" class="def">epithelium</a> or in serum PSA levels, despite a substantial increase in serum lycopene.[<a class="bk_pop" href="#CDR0000719335_rl_16_42">42</a>]</p><p id="CDR0000719335__656">In another study, 32 men with HGPIN received a lycopene-enriched diet (20–25 mg/day lycopene from triple-concentrated tomato paste) before undergoing a repeat biopsy after 6 months. No overall clinical benefit was seen in decreasing the rate of progression to prostate cancer. Baseline PSA levels showed no significant change. Prostatic lycopene concentration was the only difference between those whose repeat <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045164/" class="def">biopsy</a> showed HGPIN, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000257216/" class="def">prostatitis</a>, or prostate cancer. Prostatic lycopene concentration below 1 ng/mg was associated with prostate cancer at the 6-month follow-up biopsy (<i>P</i> = .003).[<a class="bk_pop" href="#CDR0000719335_rl_16_21">21</a>] Refer to the <a href="#CDR0000719335__485">Multicomponent Therapies</a> section of this summary for more information about trials of multicomponent therapies that include lycopene. </p></div><div id="CDR0000719335__657"><h5>Treatment</h5><div id="CDR0000719335__671" class="table"><h3><span class="title">Table 2. Clinical Trials of Lycopene for Prostate Cancer Treatment<sup>a</sup></span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK83261.13/table/CDR0000719335__671/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__CDR0000719335__671_lrgtbl__"><table class="no_margin"><thead><tr><th colspan="1" rowspan="1" style="vertical-align:top;">Patient Population/Trial Design/Sample Size</th><th colspan="1" rowspan="1" style="vertical-align:top;">Agent/Dose</th><th colspan="1" rowspan="1" style="vertical-align:top;">Duration</th><th colspan="1" rowspan="1" style="vertical-align:top;"><a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045618/" class="def">Biomarkers</a></th><th colspan="1" rowspan="1" style="vertical-align:top;">Results</th></tr></thead><tbody><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Preprostatectomy; pilot RCT; n = 26 [<a class="bk_pop" href="#CDR0000719335_rl_16_43">43</a>]</td><td colspan="1" rowspan="1" style="vertical-align:top;">Tomato oleoresin extract containing lycopene 30 mg/d (15 mg bid) or placebo control </td><td colspan="1" rowspan="1" style="vertical-align:top;">3 wk</td><td colspan="1" rowspan="1" style="vertical-align:top;">Tumor volume</td><td colspan="1" rowspan="1" style="vertical-align:top;">Smaller tumors (80% vs. 45%, less than 4 mL), less involvement of surgical margins and/or extraprostatic tissues with cancer (73% vs. 18%, organ-confined disease), and less diffuse involvement of the prostate by high-grade prostatic intraepithelial neoplasia (33% vs. 0%, focal involvement)</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Preprostatectomy; RCT; N = 79 [<a class="bk_pop" href="#CDR0000719335_rl_16_44">44</a>]</td><td colspan="1" rowspan="1" style="vertical-align:top;">Tomato products containing 30 mg of lycopene daily, tomato products plus <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045113/" class="def">selenium</a>, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045809/" class="def">omega-3 fatty acids</a>, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000407766/" class="def">soy</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046660/" class="def">isoflavones</a>, grape/<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000321386/" class="def">pomegranate</a> juice and green/black tea, or a control diet</td><td colspan="1" rowspan="1" style="vertical-align:top;">3 wk</td><td colspan="1" rowspan="1" style="vertical-align:top;">PSA</td><td colspan="1" rowspan="1" style="vertical-align:top;">No differences in PSA values between the intervention and control groups. Lower PSA values in men with intermediate-risk prostate cancer with highest increases in lycopene levels</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Preprostatectomy; RCT; n = 45 [<a class="bk_pop" href="#CDR0000719335_rl_16_45">45</a>]</td><td colspan="1" rowspan="1" style="vertical-align:top;">15 mg, 30 mg, or 45 mg lycopene vs. control</td><td colspan="1" rowspan="1" style="vertical-align:top;">30 d</td><td colspan="1" rowspan="1" style="vertical-align:top;">PSA,
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steroid hormones,
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Ki-67
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</td><td colspan="1" rowspan="1" style="vertical-align:top;">30 mg lycopene dose level decrease in free testosterone, significant increases in mean plasma estradiol and in serum sex hormone-binding globulin, and decrease in the percentage of cells expressing Ki-67; at the 45 mg/d dose, serum total estradiol increased</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Active surveillance; single arm; N = 40 [<a class="bk_pop" href="#CDR0000719335_rl_16_46">46</a>]</td><td colspan="1" rowspan="1" style="vertical-align:top;">Whole-tomato supplement containing 10 mg of lycopene (Lycoplus)</td><td colspan="1" rowspan="1" style="vertical-align:top;">1 y</td><td colspan="1" rowspan="1" style="vertical-align:top;">PSA velocity;
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PSA doubling time
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</td><td colspan="1" rowspan="1" style="vertical-align:top;">Statistically significant decrease in PSA velocity after lycopene treatment (<i>P</i> = .0007)</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Biochemical relapse after radiation therapy or surgery; RCT; N = 36 [<a class="bk_pop" href="#CDR0000719335_rl_16_47">47</a>]</td><td colspan="1" rowspan="1" style="vertical-align:top;">15, 30, 45, 60, 90, or 120 mg/d of lycopene (Lyc-O-Mato)</td><td colspan="1" rowspan="1" style="vertical-align:top;">1 y</td><td colspan="1" rowspan="1" style="vertical-align:top;">PSA</td><td colspan="1" rowspan="1" style="vertical-align:top;">Did not alter serum PSA levels</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Biochemical relapse after radiation therapy or surgery; single-arm study; N = 46 [<a class="bk_pop" href="#CDR0000719335_rl_16_48">48</a>]</td><td colspan="1" rowspan="1" style="vertical-align:top;">Tomato juice or paste containing lycopene 30 mg/d</td><td colspan="1" rowspan="1" style="vertical-align:top;">4 mo</td><td colspan="1" rowspan="1" style="vertical-align:top;">PSA</td><td colspan="1" rowspan="1" style="vertical-align:top;">Did not alter serum PSA levels except in one patient</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Metastatic, hormone-refractory prostate cancer; open label study; N = 20 [<a class="bk_pop" href="#CDR0000719335_rl_16_49">49</a>]</td><td colspan="1" rowspan="1" style="vertical-align:top;">Lycopene 10 mg/d (Lycored softules)</td><td colspan="1" rowspan="1" style="vertical-align:top;">3 mo</td><td colspan="1" rowspan="1" style="vertical-align:top;">PSA</td><td colspan="1" rowspan="1" style="vertical-align:top;">50% had PSA levels that remained stable, 15% showed biochemical progression, 30% showed a partial response, and one patient exhibited a complete response after treatment</td></tr><tr><td colspan="1" rowspan="1" style="vertical-align:top;">Hormone-refractory prostate cancer; single arm study; N = 17 [<a class="bk_pop" href="#CDR0000719335_rl_16_50">50</a>]</td><td colspan="1" rowspan="1" style="vertical-align:top;"> Lycopene 15 mg/d (pills)</td><td colspan="1" rowspan="1" style="vertical-align:top;">6 mo</td><td colspan="1" rowspan="1" style="vertical-align:top;">PSA</td><td colspan="1" rowspan="1" style="vertical-align:top;">PSA stabilization in 5 (29%) of 17 and PSA progression in 12 (71%) of 17</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">Bid = twice a day; PSA = prostate-specific antigen; RCT = randomized controlled trial.</p></div></dd><dt></dt><dd><div><p class="no_margin"><sup>a</sup>Refer to text and the <a href="https://www.cancer.gov/publications/dictionaries/cancer-terms/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NCI Dictionary of Cancer Terms</a> for additional information and definition of terms.</p></div></dd></dl></div></div></div><div id="CDR0000719335__658"><h5>Preprostatectomy </h5><p id="CDR0000719335__659">Other studies have examined the potential therapeutic effect of lycopene-containing products in men with prostate cancer. The effects of lycopene supplementation on prostate tissue and prostate cancer biomarkers were investigated in men with localized prostate cancer in a 2002 pilot study. Men received either lycopene supplements (30 mg/d) or no intervention twice daily for 3 weeks before radical prostatectomy. Men in the intervention arm had smaller tumors (80% vs. 45%, less than 4 ml), less involvement of surgical margins and/or extraprostatic tissues with cancer (73% vs. 18%, organ-confined disease), and less diffuse involvement of the prostate by HGPIN (33% vs. 0%, focal involvement) compared with men in the control group. Mean plasma PSA levels were lower in the intervention group compared with the control group.[<a class="bk_pop" href="#CDR0000719335_rl_16_43">43</a>] Refer to the <a href="#CDR0000719335__485">Multicomponent Therapies</a> section of this summary for more information on studies with lycopene.</p><p id="CDR0000719335__264">In a phase II, randomized, placebo-controlled trial,[<a class="bk_pop" href="#CDR0000719335_rl_16_45">45</a>] 45 men with clinically localized prostate cancer received either 15, 30, or 45 mg of lycopene (Lyc-O-Mato) or no supplement from time of biopsy to prostatectomy (30 days). Plasma lycopene increased from baseline to the end of treatment in all treatment groups, with the greatest increase observed in the 45 mg lycopene-supplemented arm. No toxicity was reported. Overall, men with prostate cancer had lower baseline levels of plasma lycopene, compared with disease-free controls, and similar to levels observed in previous studies in men with prostate cancer.[<a class="bk_pop" href="#CDR0000719335_rl_16_51">51</a>,<a class="bk_pop" href="#CDR0000719335_rl_16_52">52</a>] At the 30 mg lycopene dose level, a moderate decrease in mean free testosterone and significant increases in mean plasma estradiol and in serum sex hormone-binding globulin (SHBG) (<i>P</i> = .022) were observed. At the 45 mg/d dose, serum total estradiol increased (<i>P</i> = .006) with no significant change in serum testosterone. However, serum testosterone and SHBG levels in the control group remained unchanged. The mean difference between groups who received the lycopene supplementation demonstrated a lower percentage of cells expressing Ki-67, compared with the control group. Notably, 75% of subjects in the 30 mg lycopene-supplemented arm had a decrease in the percentage of cells expressing Ki-67, compared with the subjects in the control group, in which 100% of the subjects observed an increase. These changes were not <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044167/" class="def">statistically significant</a>, compared with the changes in the control arm for this sample size and duration of intervention. Although antioxidant properties of lycopene have been hypothesized to be primarily responsible for its beneficial effects, this study suggests that other mechanisms mediated by steroid hormones may also be involved.[<a class="bk_pop" href="#CDR0000719335_rl_16_45">45</a>]</p><p id="CDR0000719335__620"> In a single-arm study of previously untreated men diagnosed with localized prostate cancer, investigators determined whether PSA velocity was altered by a 1-year intervention with lycopene supplementation (10 mg/d). A statistically significant decrease in PSA velocity after lycopene treatment was observed (<i>P</i> = .0007). Analysis of the PSA-doubling time (pretreatment vs. post-treatment) showed a median increase after supplementation for 174 days; however, this was not statistically significant.[<a class="bk_pop" href="#CDR0000719335_rl_16_46">46</a>]</p><p id="CDR0000719335__42">In one study, prostate cancer patients (N = 36) who had <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000542440/" class="def">biochemical relapse</a> following <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044971/" class="def">radiation therapy</a> or surgery received lycopene supplements twice daily for 1 year. There were six cohorts in the study, each receiving a different dose of lycopene (15, 30, 45, 60, 90, or 120 mg/d). Serum PSA levels did not respond to lycopene treatment. Plasma lycopene levels rose and appeared to plateau by 3 months for all doses. The results indicate that, although lycopene may be safe and well tolerated, it did not alter serum PSA levels in biochemically relapsed prostate cancer patients.[<a class="bk_pop" href="#CDR0000719335_rl_16_47">47</a>]</p><p id="CDR0000719335__43">In a 2004 <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000285990/" class="def">open-label study</a>, patients with <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000686077/" class="def">hormone-refractory</a> prostate cancer (HRPC) (N = 20) received lycopene supplements daily (10 mg/d of lycopene) for 3 months. Of the study's participants, 50% had PSA levels that remained stable, 15% showed biochemical progression, 30% showed a <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045819/" class="def">partial response</a>, and one patient (5% of the total sample) exhibited a <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045652/" class="def">complete response</a> after treatment.[<a class="bk_pop" href="#CDR0000719335_rl_16_49">49</a>] In a <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045831/" class="def">phase II</a> study, HRPC patients took lycopene supplements daily (15 mg of lycopene/day) for 6 months. By the end of the study, serum PSA levels had almost doubled in 12 of the 17 patients, and 5 of 17 patients had achieved PSA stabilization. Although this was a small study without a <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044149/" class="def">control group</a>, the results suggest that lycopene may not be beneficial for patients with advanced prostate cancer.[<a class="bk_pop" href="#CDR0000719335_rl_16_50">50</a>]</p><p id="CDR0000719335__44">In another study, 46 patients with androgen-independent prostate cancer consumed either tomato paste or tomato juice daily (both preparations provided 30 mg of lycopene/d) for at least 4 months. Only one patient in this study exhibited a decrease in PSA level. Several episodes of gastrointestinal side effects were noted after eating the tomato paste or drinking the tomato juice.[<a class="bk_pop" href="#CDR0000719335_rl_16_48">48</a>]</p><p id="CDR0000719335__629">On the basis of the available evidence, early randomized clinical trials with lycopene as a single agent, in tomato products, and in combination with other agents (fish oil supplements, tomato products plus selenium, omega-3 fatty acids, soy isoflavones, grape/pomegranate juice and green/black tea) demonstrates bioavailability in serum and modulation of intermediate biomarkers implicated in prostate carcinogenesis and prostate cancer progression in most studies. Perhaps, future clinical trials should include longer duration of consistent lycopene exposure, while accounting for variations in individual absorption of carotenoids and <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000769472/" class="def">heterogeneity</a> of high-risk (HGPIN, atypical small acinar proliferation) and prostate cancer patient populations (indolent vs. aggressive prostate cancer or androgen-dependent vs. androgen-independent prostate cancer). </p></div></div></div><div id="CDR0000719335__164"><h4>Current clinical trials</h4><p id="CDR0000719335__165">Check NCI’s list of cancer clinical trials for CAM clinical trials on <a href="https://www.cancer.gov/about-cancer/treatment/clinical-trials/search/results?protocolsearchid=10180800&vers=1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">lycopene for prostate cancer</a> that are actively enrolling patients.</p><p id="CDR0000719335__166">General information about clinical trials is also available from the <a href="https://www.cancer.gov/about-cancer/treatment/clinical-trials" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NCI website</a>.</p></div></div><div id="CDR0000719335__14"><h3>Adverse Effects</h3><p id="CDR0000719335__15">Studies evaluating lycopene in randomized clinical trials targeting men at high risk for prostate cancer and populations with prostate cancer have indicated relatively few toxicities at the dose and duration of intervention.[<a class="bk_pop" href="#CDR0000719335_rl_16_38">38</a>,<a class="bk_pop" href="#CDR0000719335_rl_16_40">40</a>,<a class="bk_pop" href="#CDR0000719335_rl_16_41">41</a>,<a class="bk_pop" href="#CDR0000719335_rl_16_46">46</a>,<a class="bk_pop" href="#CDR0000719335_rl_16_49">49</a>] Doses of lycopene ranging between 8 mg and 45 mg administered over a period ranging from 3 weeks to 2 years have been reported to be safe in randomized clinical trials targeting the prostate. When <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044922/" class="def">adverse effects</a> occurred, they tended to present as gastrointestinal symptoms [<a class="bk_pop" href="#CDR0000719335_rl_16_48">48</a>] and, in one study, the symptoms resolved when lycopene was taken with meals.[<a class="bk_pop" href="#CDR0000719335_rl_16_50">50</a>] Another study reported that one participant withdrew because of <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000306496/" class="def">diarrhea</a>.[<a class="bk_pop" href="#CDR0000719335_rl_16_47">47</a>]</p><p id="CDR0000719335__46">The FDA has accepted the determination by various companies that their lycopene-containing products meet the FDA’s requirements for the designation of GRAS.[<a class="bk_pop" href="#CDR0000719335_rl_16_53">53</a>]</p></div><div id="CDR0000719335_rl_16"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000719335_rl_16_1">Kopec R, Schwartz SJ, Hadley C: Lycopene. 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[<a href="/pmc/articles/PMC3070045/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3070045</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/21335507" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21335507</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_16_23">Karppi J, Kurl S, Nurmi T, et al.: Serum lycopene and the risk of cancer: the Kuopio Ischaemic Heart Disease Risk Factor (KIHD) study. Ann Epidemiol 19 (7): 512-8, 2009. [<a href="https://pubmed.ncbi.nlm.nih.gov/19443241" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19443241</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_16_24">Etminan M, Takkouche B, Caamaño-Isorna F: The role of tomato products and lycopene in the prevention of prostate cancer: a meta-analysis of observational studies. Cancer Epidemiol Biomarkers Prev 13 (3): 340-5, 2004. [<a href="https://pubmed.ncbi.nlm.nih.gov/15006906" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15006906</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_16_25">Chen J, Song Y, Zhang L: Lycopene/tomato consumption and the risk of prostate cancer: a systematic review and meta-analysis of prospective studies. J Nutr Sci Vitaminol (Tokyo) 59 (3): 213-23, 2013. [<a href="https://pubmed.ncbi.nlm.nih.gov/23883692" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23883692</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_16_26">Kirsh VA, Mayne ST, Peters U, et al.: A prospective study of lycopene and tomato product intake and risk of prostate cancer. Cancer Epidemiol Biomarkers Prev 15 (1): 92-8, 2006. [<a href="https://pubmed.ncbi.nlm.nih.gov/16434593" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16434593</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_16_27">Peters U, Leitzmann MF, Chatterjee N, et al.: Serum lycopene, other carotenoids, and prostate cancer risk: a nested case-control study in the prostate, lung, colorectal, and ovarian cancer screening trial. Cancer Epidemiol Biomarkers Prev 16 (5): 962-8, 2007. [<a href="https://pubmed.ncbi.nlm.nih.gov/17507623" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17507623</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_16_28">Zu K, Mucci L, Rosner BA, et al.: Dietary lycopene, angiogenesis, and prostate cancer: a prospective study in the prostate-specific antigen era. J Natl Cancer Inst 106 (2): djt430, 2014. [<a href="/pmc/articles/PMC3952200/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3952200</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/24463248" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24463248</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_16_29">Nordström T, Van Blarigan EL, Ngo V, et al.: Associations between circulating carotenoids, genomic instability and the risk of high-grade prostate cancer. Prostate 76 (4): 339-48, 2016. [<a href="/pmc/articles/PMC5493324/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5493324</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/26585352" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26585352</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_16_30">Antwi SO, Steck SE, Su LJ, et al.: Carotenoid intake and adipose tissue carotenoid levels in relation to prostate cancer aggressiveness among African-American and European-American men in the North Carolina-Louisiana prostate cancer project (PCaP). Prostate 76 (12): 1053-66, 2016. [<a href="/pmc/articles/PMC5080909/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5080909</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/27271547" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 27271547</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_16_31">Antwi SO, Steck SE, Zhang H, et al.: Plasma carotenoids and tocopherols in relation to prostate-specific antigen (PSA) levels among men with biochemical recurrence of prostate cancer. Cancer Epidemiol 39 (5): 752-62, 2015. [<a href="/pmc/articles/PMC4577465/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4577465</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/26165176" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26165176</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_16_32">Wang Y, Jacobs EJ, Newton CC, et al.: Lycopene, tomato products and prostate cancer-specific mortality among men diagnosed with nonmetastatic prostate cancer in the Cancer Prevention Study II Nutrition Cohort. Int J Cancer 138 (12): 2846-55, 2016. [<a href="https://pubmed.ncbi.nlm.nih.gov/26830232" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26830232</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_16_33">Borel P, Desmarchelier C, Nowicki M, et al.: Lycopene bioavailability is associated with a combination of genetic variants. Free Radic Biol Med 83: 238-44, 2015. [<a href="https://pubmed.ncbi.nlm.nih.gov/25772008" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25772008</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_16_34">Grainger EM, Hadley CW, Moran NE, et al.: A comparison of plasma and prostate lycopene in response to typical servings of tomato soup, sauce or juice in men before prostatectomy. Br J Nutr 114 (4): 596-607, 2015. [<a href="/pmc/articles/PMC7224633/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC7224633</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/26202168" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26202168</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_16_35">Brown MJ, Ferruzzi MG, Nguyen ML, et al.: Carotenoid bioavailability is higher from salads ingested with full-fat than with fat-reduced salad dressings as measured with electrochemical detection. Am J Clin Nutr 80 (2): 396-403, 2004. [<a href="https://pubmed.ncbi.nlm.nih.gov/15277161" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15277161</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_16_36">Fielding JM, Rowley KG, Cooper P, et al.: Increases in plasma lycopene concentration after consumption of tomatoes cooked with olive oil. Asia Pac J Clin Nutr 14 (2): 131-6, 2005. [<a href="https://pubmed.ncbi.nlm.nih.gov/15927929" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15927929</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_16_37">Lee A, Thurnham DI, Chopra M: Consumption of tomato products with olive oil but not sunflower oil increases the antioxidant activity of plasma. Free Radic Biol Med 29 (10): 1051-5, 2000. [<a href="https://pubmed.ncbi.nlm.nih.gov/11084294" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11084294</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_16_38">Talvas J, Caris-Veyrat C, Guy L, et al.: Differential effects of lycopene consumed in tomato paste and lycopene in the form of a purified extract on target genes of cancer prostatic cells. Am J Clin Nutr 91 (6): 1716-24, 2010. [<a href="https://pubmed.ncbi.nlm.nih.gov/20392890" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20392890</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_16_39">Kim HS, Bowen P, Chen L, et al.: Effects of tomato sauce consumption on apoptotic cell death in prostate benign hyperplasia and carcinoma. Nutr Cancer 47 (1): 40-7, 2003. [<a href="https://pubmed.ncbi.nlm.nih.gov/14769536" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 14769536</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_16_40">Mohanty NK, Saxena S, Singh UP, et al.: Lycopene as a chemopreventive agent in the treatment of high-grade prostate intraepithelial neoplasia. Urol Oncol 23 (6): 383-5, 2005 Nov-Dec. [<a href="https://pubmed.ncbi.nlm.nih.gov/16301113" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16301113</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_16_41">Bunker CH, McDonald AC, Evans RW, et al.: A randomized trial of lycopene supplementation in Tobago men with high prostate cancer risk. Nutr Cancer 57 (2): 130-7, 2007. [<a href="https://pubmed.ncbi.nlm.nih.gov/17571945" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17571945</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_16_42">Gann PH, Deaton RJ, Rueter EE, et al.: A Phase II Randomized Trial of Lycopene-Rich Tomato Extract Among Men with High-Grade Prostatic Intraepithelial Neoplasia. Nutr Cancer 67 (7): 1104-12, 2015. [<a href="/pmc/articles/PMC4736719/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4736719</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/26422197" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26422197</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_16_43">Kucuk O, Sarkar FH, Djuric Z, et al.: Effects of lycopene supplementation in patients with localized prostate cancer. Exp Biol Med (Maywood) 227 (10): 881-5, 2002. [<a href="https://pubmed.ncbi.nlm.nih.gov/12424329" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12424329</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_16_44">Paur I, Lilleby W, Bøhn SK, et al.: Tomato-based randomized controlled trial in prostate cancer patients: Effect on PSA. Clin Nutr 36 (3): 672-679, 2017. [<a href="https://pubmed.ncbi.nlm.nih.gov/27406859" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 27406859</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_16_45">Kumar NB, Besterman-Dahan K, Kang L, et al.: Results of a Randomized Clinical Trial of the Action of Several Doses of Lycopene in Localized Prostate Cancer: Administration Prior to Radical Prostatectomy. Clin Med Urol 1: 1-14, 2008. [<a href="/pmc/articles/PMC2846655/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2846655</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/20354574" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20354574</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_16_46">Barber NJ, Zhang X, Zhu G, et al.: Lycopene inhibits DNA synthesis in primary prostate epithelial cells in vitro and its administration is associated with a reduced prostate-specific antigen velocity in a phase II clinical study. Prostate Cancer Prostatic Dis 9 (4): 407-13, 2006. [<a href="https://pubmed.ncbi.nlm.nih.gov/16983396" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16983396</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_16_47">Clark PE, Hall MC, Borden LS Jr, et al.: Phase I-II prospective dose-escalating trial of lycopene in patients with biochemical relapse of prostate cancer after definitive local therapy. Urology 67 (6): 1257-61, 2006. [<a href="https://pubmed.ncbi.nlm.nih.gov/16765186" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16765186</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_16_48">Jatoi A, Burch P, Hillman D, et al.: A tomato-based, lycopene-containing intervention for androgen-independent prostate cancer: results of a Phase II study from the North Central Cancer Treatment Group. Urology 69 (2): 289-94, 2007. [<a href="https://pubmed.ncbi.nlm.nih.gov/17320666" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17320666</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_16_49">Ansari MS, Gupta NP: Lycopene: a novel drug therapy in hormone refractory metastatic prostate cancer. Urol Oncol 22 (5): 415-20, 2004 Sep-Oct. [<a href="https://pubmed.ncbi.nlm.nih.gov/15464923" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15464923</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_16_50">Schwenke C, Ubrig B, Thürmann P, et al.: Lycopene for advanced hormone refractory prostate cancer: a prospective, open phase II pilot study. J Urol 181 (3): 1098-103, 2009. [<a href="https://pubmed.ncbi.nlm.nih.gov/19150092" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19150092</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_16_51">Gann PH, Ma J, Giovannucci E, et al.: Lower prostate cancer risk in men with elevated plasma lycopene levels: results of a prospective analysis. Cancer Res 59 (6): 1225-30, 1999. [<a href="https://pubmed.ncbi.nlm.nih.gov/10096552" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10096552</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_16_52">Giovannucci E, Ascherio A, Rimm EB, et al.: Intake of carotenoids and retinol in relation to risk of prostate cancer. J Natl Cancer Inst 87 (23): 1767-76, 1995. [<a href="https://pubmed.ncbi.nlm.nih.gov/7473833" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7473833</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_16_53">Generally Recognized as Safe (GRAS) Notice Inventory. Silver Spring, Md: Food and Drug Administration, 2011. <a href="http://www.accessdata.fda.gov/scripts/fcn/fcnNavigation.cfm?rpt=grasListing" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">Available online</a>. Last accessed April 7, 2017.</div></li></ol></div></div><div id="CDR0000719335__161"><h2 id="_CDR0000719335__161_">Modified Citrus Pectin</h2><div id="CDR0000719335__60"><h3>Overview</h3><p id="CDR0000719335__61">This section contains the following key information:</p><ul id="CDR0000719335__62"><li class="half_rhythm"><div>Citrus pectin (CP) is a complex <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044162/" class="def">polysaccharide</a> found in the peel and pulp of citrus fruit and can be modified by treatment with high pH and temperature.</div></li><li class="half_rhythm"><div><a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044517/" class="def">Preclinical</a> research suggests that modified citrus pectin (MCP) may have effects on <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045333/" class="def">cancer</a> growth and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046710/" class="def">metastasis</a> through multiple potential mechanisms.</div></li><li class="half_rhythm"><div>Very limited <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044195/" class="def">clinical</a> research has been done with a couple of CP-containing products. For <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000445079/" class="def">prostate cancer</a> patients, the results suggest some potential clinical benefits with relatively minor and infrequent <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000444960/" class="def">adverse events</a>.</div></li></ul></div><div id="CDR0000719335__63"><h3>General Information and History</h3><p id="CDR0000719335__64">Pectin is a complex polysaccharide contained in the primary <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046476/" class="def">cell</a> walls of terrestrial plants. The word ‘pectin’ comes from the Greek word for congealed or curdled. Plant pectin is used in food processing as a gelling agent and also in the formulation of <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044068/" class="def">oral</a> and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045927/" class="def">topical</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000482419/" class="def">medicines</a> as a stabilizer and nonbiodegradable matrix to support controlled <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000348921/" class="def">drug</a> delivery.[<a class="bk_pop" href="#CDR0000719335_rl_161_1">1</a>] CP is found in the peel and pulp of citrus fruit and can be modified by treatment with high pH and temperature.[<a class="bk_pop" href="#CDR0000719335_rl_161_2">2</a>] Modification results in shorter <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045065/" class="def">molecules</a> that dissolve better in water and are more readily absorbed by the body than are complex, longer chain CPs.[<a class="bk_pop" href="#CDR0000719335_rl_161_3">3</a>] One of the molecular targets of MCP is galectin-3, a <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046092/" class="def">protein</a> found on the surface and within mammalian cells that is involved in many cellular processes, including cell adhesion, cell activation and chemoattraction, cell growth and differentiation, the <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000597111/" class="def">cell cycle</a>, and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046524/" class="def">apoptosis</a>; MCP inhibits galectin-3 activity.[<a class="bk_pop" href="#CDR0000719335_rl_161_2">2</a>]</p><p id="CDR0000719335__147">Some research suggests that MCP may be protective against various types of cancer, including <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044237/" class="def">colon</a>, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000445043/" class="def">lung</a>, and prostate cancer. MCP may exert its anticancer effects by interfering with <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046634/" class="def">tumor</a> cell metastasis or by inducing apoptosis.[<a class="bk_pop" href="#CDR0000719335_rl_161_4">4</a>]</p><p id="CDR0000719335__148">MCP was also shown to <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000043976/" class="def">activate</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044062/" class="def">natural killer cells</a> in <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045343/" class="def">leukemic</a> cell cultures, suggesting it may be able to stimulate the <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046356/" class="def">immune system</a>.[<a class="bk_pop" href="#CDR0000719335_rl_161_5">5</a>]</p></div><div id="CDR0000719335__65"><h3>Preclinical Studies/Animal Studies</h3><div id="CDR0000719335__66"><h4><i>In vitro</i> studies</h4><p id="CDR0000719335__67">In a 2007 study, pectins were investigated for their anticancer properties. Prostate cancer cells were treated with three different pectins; CP, Pectasol (PeS, a <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000373932/" class="def">dietary supplement</a> containing MCP), and fractionated pectin powder (FPP). FPP induced apoptosis to a much greater degree than did CP and PeS. Further analysis revealed that treating prostate cancer cells with heated CP resulted in levels of apoptosis similar to those following treatment with FPP. This suggests that specific structural features of pectin may be responsible for its ability to induce apoptosis in prostate cancer cells.[<a class="bk_pop" href="#CDR0000719335_rl_161_4">4</a>]</p><p id="CDR0000719335__68">In a 2010 study, prostate cancer cells were treated with PeS or PectaSol-C, the only two MCPs previously used in human trials. The researchers postulated that, because it has a lower molecular weight, PectaSol-C may have better <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044225/" class="def">bioavailability</a> than PeS. Both types of MCP were tested at a <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000683342/" class="def">concentration</a> of 1 mg/mL and both were effective in inhibiting cell growth and inducing apoptosis through inhibition of the MAPK/ERK <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000561720/" class="def">signaling pathway</a> and activation of the <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046081/" class="def">enzyme</a> caspase-3.[<a class="bk_pop" href="#CDR0000719335_rl_161_6">6</a>]</p><p id="CDR0000719335__69">In one study, the role of galectin-3, a multifunctional <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044026/" class="def">endogenous</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044051/" class="def">lectin</a>, in <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045230/" class="def">cisplatin</a>-treated prostate cancer cells was examined. Prostate cancer cells that expressed galectin-3 were found to be resistant to the apoptotic effects of cisplatin. However, cells that did not express galectin-3 (via silencing <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046568/" class="def">RNA</a> knockdown of galectin-3 expression or treatment with MCP) were susceptible to cisplatin-induced apoptosis. These findings suggest that galectin-3 expression may play a role in prostate cancer cell chemoresistance and that the <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000346517/" class="def">efficacy</a> of cisplatin treatment in prostate cancer may be improved by inhibiting galectin-3.[<a class="bk_pop" href="#CDR0000719335_rl_161_7">7</a>]</p></div><div id="CDR0000719335__70"><h4>Animal studies</h4><p id="CDR0000719335__71">Only a few studies have been reported on the effects of MCP in animals bearing <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000285636/" class="def">implanted</a> cancers and only one involving prostate cancer.[<a class="bk_pop" href="#CDR0000719335_rl_161_8">8</a>,<a class="bk_pop" href="#CDR0000719335_rl_161_9">9</a>] The prostate cancer study examined the effects of MCP on the metastasis of prostate cancer cells injected into rats. In the study, rats were given 0.0%, 0.01%, 0.1%, or 1.0% MCP (wt/vol) in their drinking water beginning 4 days after cancer cell injection. The analysis revealed that treatment with 0.1% and 1.0% MCP resulted in <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044167/" class="def">statistically significant</a> reductions in lung metastases but did not affect <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045847/" class="def">primary tumor</a> growth.[<a class="bk_pop" href="#CDR0000719335_rl_161_9">9</a>]</p></div></div><div id="CDR0000719335__72"><h3>Human Studies</h3><div id="CDR0000719335__73"><h4>Intervention studies</h4><p id="CDR0000719335__74">In a 2007 <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045838/" class="def">pilot study</a>, patients with <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000478743/" class="def">advanced</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045301/" class="def">solid tumors</a> (various types of cancers were represented, including prostate cancer) received MCP (5 g MCP powder dissolved in water) 3 times a day for at least 8 weeks. Following treatment, improvements were reported in some measures of <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045417/" class="def">quality of life</a>, including physical functioning, global health status, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000321374/" class="def">fatigue</a>, pain, and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044043/" class="def">insomnia</a>. In addition, 22.5% of participants had <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045884/" class="def">stable disease</a> after 8 weeks of MCP treatment, and 12.3% of participants had disease stabilization lasting more than 24 weeks.[<a class="bk_pop" href="#CDR0000719335_rl_161_3">3</a>]</p><p id="CDR0000719335__75">The effect of MCP on <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046540/" class="def">prostate-specific antigen</a> (PSA) doubling time (PSADT) was investigated in a 2003 study. Prostate cancer patients with rising PSA levels received six PeS capsules 3 times a day (totaling 14.4 g of MCP powder daily) for 12 months. Following treatment, 7 of 10 patients had a statistically significant (<i>P</i> ≤ .05) increase in PSADT.[<a class="bk_pop" href="#CDR0000719335_rl_161_10">10</a>]</p></div><div id="CDR0000719335__181"><h4>Current clinical trials</h4><p id="CDR0000719335__182">Check NCI’s list of cancer clinical trials for CAM clinical trials on <a href="https://www.cancer.gov/about-cancer/treatment/clinical-trials/search/results?protocolsearchid=10924711&vers=1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">modified citrus pectin for prostate cancer</a> that are actively enrolling patients.</p><p id="CDR0000719335__183">General information about clinical trials is also available from the <a href="https://www.cancer.gov/about-cancer/treatment/clinical-trials" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NCI website</a>.</p></div></div><div id="CDR0000719335__76"><h3>Adverse Effects</h3><p id="CDR0000719335__77">In one <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044079/" class="def">prospective</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045838/" class="def">pilot study</a>, MCP was well tolerated by the majority of treated patients, with the most commonly reported <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046580/" class="def">side effects</a> being <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000446534/" class="def">pruritus</a>, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044200/" class="def">dyspepsia</a>, and flatulence.[<a class="bk_pop" href="#CDR0000719335_rl_161_3">3</a>] In another study, no serious side effects from MCP were reported, although three patients withdrew from the study due to abdominal cramps and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000306496/" class="def">diarrhea</a> that improved once treatment was halted.[<a class="bk_pop" href="#CDR0000719335_rl_161_10">10</a>]</p></div><div id="CDR0000719335_rl_161"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000719335_rl_161_1">Mohnen D: Pectin structure and biosynthesis. Curr Opin Plant Biol 11 (3): 266-77, 2008. [<a href="https://pubmed.ncbi.nlm.nih.gov/18486536" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18486536</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_161_2">Glinsky VV, Raz A: Modified citrus pectin anti-metastatic properties: one bullet, multiple targets. Carbohydr Res 344 (14): 1788-91, 2009. [<a href="/pmc/articles/PMC2782490/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2782490</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19061992" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19061992</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_161_3">Azemar M, Hildenbrand B, Haering B, et al.: Clinical benefit in patients with advanced solid tumors treated with modified citrus pectin: a prospective pilot study. Clin Med Oncol 1: 73-80, 2007. <a href="http://www.dreliaz.org/wp-content/uploads/research/Azemar-Advanced-Solid-Tumors-PectaSol-C-Clinical-Oncology.pdf" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">Available online</a>. Last accessed April 7, 2017.</div></li><li><div class="bk_ref" id="CDR0000719335_rl_161_4">Jackson CL, Dreaden TM, Theobald LK, et al.: Pectin induces apoptosis in human prostate cancer cells: correlation of apoptotic function with pectin structure. Glycobiology 17 (8): 805-19, 2007. [<a href="https://pubmed.ncbi.nlm.nih.gov/17513886" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17513886</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_161_5">Ramachandran C, Wilk BJ, Hotchkiss A, et al.: Activation of human T-helper/inducer cell, T-cytotoxic cell, B-cell, and natural killer (NK)-cells and induction of natural killer cell activity against K562 chronic myeloid leukemia cells with modified citrus pectin. BMC Complement Altern Med 11: 59, 2011. [<a href="/pmc/articles/PMC3161912/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3161912</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/21816083" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21816083</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_161_6">Yan J, Katz A: PectaSol-C modified citrus pectin induces apoptosis and inhibition of proliferation in human and mouse androgen-dependent and- independent prostate cancer cells. Integr Cancer Ther 9 (2): 197-203, 2010. [<a href="https://pubmed.ncbi.nlm.nih.gov/20462856" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20462856</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_161_7">Wang Y, Nangia-Makker P, Balan V, et al.: Calpain activation through galectin-3 inhibition sensitizes prostate cancer cells to cisplatin treatment. Cell Death Dis 1: e101, 2010. [<a href="/pmc/articles/PMC3032324/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3032324</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/21368866" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21368866</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_161_8">Hayashi A, Gillen AC, Lott JR: Effects of daily oral administration of quercetin chalcone and modified citrus pectin on implanted colon-25 tumor growth in Balb-c mice. Altern Med Rev 5 (6): 546-52, 2000. [<a href="https://pubmed.ncbi.nlm.nih.gov/11134977" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11134977</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_161_9">Pienta KJ, Naik H, Akhtar A, et al.: Inhibition of spontaneous metastasis in a rat prostate cancer model by oral administration of modified citrus pectin. J Natl Cancer Inst 87 (5): 348-53, 1995. [<a href="https://pubmed.ncbi.nlm.nih.gov/7853416" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7853416</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_161_10">Guess BW, Scholz MC, Strum SB, et al.: Modified citrus pectin (MCP) increases the prostate-specific antigen doubling time in men with prostate cancer: a phase II pilot study. Prostate Cancer Prostatic Dis 6 (4): 301-4, 2003. [<a href="https://pubmed.ncbi.nlm.nih.gov/14663471" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 14663471</span></a>]</div></li></ol></div></div><div id="CDR0000719335__162"><h2 id="_CDR0000719335__162_">Pomegranate</h2><div id="CDR0000719335__79"><h3>Overview</h3><p id="CDR0000719335__80">This section contains the following key information:</p><ul id="CDR0000719335__81"><li class="half_rhythm"><div>The <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000321386/" class="def">pomegranate</a> (<i>Punica granatum </i>L.) is native to Asia and cultivated widely throughout world.</div></li><li class="half_rhythm"><div>Various components of the pomegranate fruit contain <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045787/" class="def">minerals</a> and bioactive <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000256573/" class="def">polyphenolic</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000422394/" class="def">compounds</a>, in particular structurally distinct ellagitannins and derivatives, such as alpha-/beta-punicalagin, punicalin, and punigluconin.</div></li><li class="half_rhythm"><div>Pomegranate juice and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000407760/" class="def">extract</a>, as well as some of their bioactive components, inhibit the proliferation of various <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000445079/" class="def">prostate cancer</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044016/" class="def">cell lines</a>
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<i><a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045733/" class="def">in vitro</a></i> and induce <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046524/" class="def">apoptotic</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046476/" class="def">cell</a> death in a <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044110/" class="def">dose-dependent</a> manner.</div></li><li class="half_rhythm"><div>Cytochrome P450 <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046081/" class="def">enzyme</a> inhibition and effects on <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000653119/" class="def">insulin-like growth factor</a> binding <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046092/" class="def">protein</a>-3 (IGFBP-3) have been identified as being involved in the <i>in vitro</i> activity.</div></li><li class="half_rhythm"><div>Studies in rodent models of prostate cancer have shown that <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044100/" class="def">ingestion</a> of pomegranate juice can decrease the rate of development, growth, and spread of prostate cancer.</div></li><li class="half_rhythm"><div>The only fully reported <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045961/" class="def">clinical trial</a> of the use of pomegranate juice in men with prostate cancer showed that, on average, study participants who drank the juice had an increase in their <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046540/" class="def">prostate-specific antigen</a> (PSA) <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000306523/" class="def">doubling time</a> (PSADT).</div></li><li class="half_rhythm"><div>No serious <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044922/" class="def">adverse effects</a> have been reported in clinical trials of pomegranate juice <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000478733/" class="def">administration</a> (8 oz per day for up to 33 months).</div></li><li class="half_rhythm"><div>A <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045831/" class="def">phase II</a> study reported that pomegranate extract was associated with an increase of at least 6 month in PSADT in both treatment arms (different doses), without adverse effects. However, a phase III placebo-controlled trial of pomegranate juice and extract did not show a significant increase in PSADT.</div></li></ul></div><div id="CDR0000719335__82"><h3>General Information and History</h3><p id="CDR0000719335__83">The pomegranate (<i>Punica granatum</i> L.) is a member of the Punicaceae family native to Asia (from Iran to northern India) and cultivated throughout the Mediterranean, Southeast Asia, the East Indies, Africa, and the United States.[<a class="bk_pop" href="#CDR0000719335_rl_162_1">1</a>] The history of the pomegranate goes back centuries—the fruit is considered sacred by many religions and has been used for medicinal purposes since ancient times.[<a class="bk_pop" href="#CDR0000719335_rl_162_2">2</a>] The fruit is comprised of peel (pericarp), seeds, and aril (outer layer surrounding the seeds). The peel makes up 50% of the fruit and contains minerals and a number of bioactive polyphenolic <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000422394/" class="def">compounds</a>, in particular structurally distinct ellagitannins and derivatives, such as alpha-/beta-punicalagin, punicalin, and punigluconin. The arils are mainly composed of water and also contain phenolics and flavonoids. Anthocyanins, which are flavonoids present in arils, are responsible for the red color of the fruit and its juice.[<a class="bk_pop" href="#CDR0000719335_rl_162_3">3</a>] The majority of <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000043997/" class="def">antioxidant</a> activity comes from ellagitannins.[<a class="bk_pop" href="#CDR0000719335_rl_162_4">4</a>] It has been shown that conversion of pomegranate ellagitannins by gut microbes produces a variety of <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000462687/" class="def">metabolites</a>, such as the urolithins.[<a class="bk_pop" href="#CDR0000719335_rl_162_5">5</a>]</p><p id="CDR0000719335__84">Research studies suggest that pomegranates have beneficial effects on a number of health conditions, including <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044005/" class="def">cardiovascular</a> disease,[<a class="bk_pop" href="#CDR0000719335_rl_162_6">6</a>] and may also have positive effects on <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044068/" class="def">oral</a> or dental health.[<a class="bk_pop" href="#CDR0000719335_rl_162_7">7</a>]</p></div><div id="CDR0000719335__85"><h3>Preclinical Studies/Animal Studies</h3><p id="CDR0000719335__87"><div class="milestone-start" id="CDR0000719335__86"></div>Research studies in the laboratory have examined the effects of pomegranate on many prostate cancer cell lines and in rodent models of the disease.</p><div id="CDR0000719335__88"><h4><i>In vitro</i> studies</h4><p id="CDR0000719335__89">Ellagitannins (the main polyphenols in pomegranate juice) are hydrolyzed to ellagic <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000642987/" class="def">acid</a>, and then to urolithin A (UA) derivatives. According to a <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046683/" class="def">tissue</a> distribution experiment in wild-type mice, the prostate <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046386/" class="def">gland</a> rapidly takes up high concentrations of UA after oral or <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046339/" class="def">intraperitoneal</a> administration (0.3 mg/mouse/dose). Ellagic acid (EA) was detected in the prostate following intraperitoneal, but not oral, administration of pomegranate extract (0.8 mg/mouse/dose).[<a class="bk_pop" href="#CDR0000719335_rl_162_8">8</a>]</p><p id="CDR0000719335__90">Treating human prostate cancer cells with individual components of the pomegranate fruit has been shown to inhibit cell growth.[<a class="bk_pop" href="#CDR0000719335_rl_162_9">9</a>-<a class="bk_pop" href="#CDR0000719335_rl_162_12">12</a>] In one study, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000597120/" class="def">dihydrotestosterone</a>-stimulated LNCaP cells were treated with 13 pomegranate compounds at various concentrations (0-100 <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000659790/" class="def">µM</a>).[<a class="bk_pop" href="#CDR0000719335_rl_162_10">10</a>] Four of the 13 compounds, epigallocatechin gallate (EGCG), delphinidin chloride, kaempferol, and punicic acid, exhibited an ability to inhibit cell growth in a dose-dependent manner. Treating cells with EGCG, kaempferol, and punicic acid further resulted in apoptosis, with punicic acid (the primary constituent of pomegranate seeds) being the strongest inducer of apoptosis. Additionally, findings from this study suggested that punicic acid may activate apoptosis by a caspase-dependent pathway.[<a class="bk_pop" href="#CDR0000719335_rl_162_10">10</a>]</p><p id="CDR0000719335__91">Pomegranate extracts have also been shown to inhibit the proliferation of human prostate cancer cells <i>in vitro</i>.[<a class="bk_pop" href="#CDR0000719335_rl_162_11">11</a>,<a class="bk_pop" href="#CDR0000719335_rl_162_13">13</a>,<a class="bk_pop" href="#CDR0000719335_rl_162_14">14</a>] In one study, three prostate cancer cell lines (LNCaP, LNCaP-AR, and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000390267/" class="def">DU-145</a>) were treated with pomegranate polyphenols [punicalagin (PA) or EA], a pomegranate extract (POMx, which contains EA and PA), or pomegranate juice (PJ, which contains PA, EA, and anthocyanins) in concentrations ranging from 3.125 to 50 µg/mL (standardized to PA content). All four treatments resulted in <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044167/" class="def">statistically significant</a> increases in apoptosis and dose-dependent decreases in <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046479/" class="def">cell proliferation</a> in the three cell lines. However, PJ and POMx were stronger inhibitors of cell growth than were PA and EA. In this study, the effects of PA, EA, POMx, and PJ on the expression of <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045592/" class="def">androgen</a>-synthesizing enzyme <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000045693/" class="def">genes</a> and the androgen <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044958/" class="def">receptor</a> were also measured. Although statistically significant decreases in <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000537335/" class="def">gene expression</a> occurred in LNCaP cells following treatment with POMx and in DU-145 cells following treatment with EA and POMx, significant decreases in gene expression and androgen receptor occurred in LNCaP-AR cells following all of the treatments.[<a class="bk_pop" href="#CDR0000719335_rl_162_11">11</a>] In a second study, treating PC3 cells (human prostate cancer cells with a high <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044058/" class="def">metastatic</a> potential) with POMx (10-100 µg/mL) resulted in cell growth inhibition and apoptosis, both in a dose-dependent manner. Treatment of CWR22Rv1 cells (prostate cancer cells that express the androgen receptor and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000643082/" class="def">secrete</a> PSA) with POMx (10-100 µg/mL concentrations of pomegranate fruit extract) led to the inhibition of cell growth, a dose-dependent decrease in androgen receptor <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000557359/" class="def">protein expression</a>, and dose-dependent reductions in PSA protein levels.[<a class="bk_pop" href="#CDR0000719335_rl_162_14">14</a>]</p><p id="CDR0000719335__92">The enzyme cytochrome P450 (CYP1B1) has been implicated in cancer development and progression. As a result, CYP1B1 inhibitors may be effective anticarcinogenic targets. In a study reported in 2009, the effects of pomegranate metabolites on CYP1B1 activation and expression in CWR22Rv1 prostate cancer cells were examined. In this study, urolithins A and B inhibited CYP1B1 expression and activity.[<a class="bk_pop" href="#CDR0000719335_rl_162_15">15</a>]</p><p id="CDR0000719335__93">In addition, the insulin-like growth factor (IGF) system has been implicated in prostate cancer. A study reported in 2010 examined the effects of a POMx on the IGF system. Treating LAPC4 prostate cancer cells with POMx (10 µg/mL concentration of pomegranate extract prepared from skin and arils minus seeds) resulted in cell growth inhibition and apoptosis, but treating the cells with both reagents led to larger effects on growth inhibition and apoptosis. However, these substances may have induced apoptosis by different mechanisms. Other findings suggested that POMx treatment reduced <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000653126/" class="def">mTOR</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000641137/" class="def">phosphorylation</a> at Ser2448 and Ser2481, whereas IGFBP-3 increased phosphorylation at those sites. In addition, CWR22Rv1 cells treated with POMx (1 and 10 µg/mL) exhibited a dose-dependent reduction in IGF1 <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000662001/" class="def">mRNA</a> levels, but treatment with IGFBP-3 or IGF-1 did not alter levels of IGF1; these results suggest that one way POMx decreases prostate cancer cell survival is by inhibiting IGF1 expression.[<a class="bk_pop" href="#CDR0000719335_rl_162_13">13</a>]</p><p id="CDR0000719335__94">In a study reported in 2011, human <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045713/" class="def">hormone</a>-independent prostate cancer cells (DU145 and PC3 cell lines) were treated with 1% or 5% PJ for times ranging from 12 to 72 hours. The results showed that treatment with PJ increased adhesion and decreased the migration of prostate cancer cells. Molecular analyses revealed that PJ increased the expression of cell-adhesion related genes and inhibited the expression of genes involved in cytoskeletal function and cellular migration. These findings suggested that PJ may be beneficial in slowing down or preventing cancer cell metastasis.[<a class="bk_pop" href="#CDR0000719335_rl_162_16">16</a>]</p></div><div id="CDR0000719335__95"><h4>Animal studies</h4><p id="CDR0000719335__96">The effects of pomegranate on prostate cancer have been examined using a number of rodent models of the disease. In one study, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044579/" class="def">athymic nude mice</a> were <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044678/" class="def">injected</a> with tumor-forming cells. Following inoculation, animals were randomly assigned to receive normal drinking water or PJ (0.1% or 0.2% POMx in drinking water, which resulted in an intake corresponding to 250 or 500 mL of PJ per day for an average adult human). Small, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045301/" class="def">solid tumors</a> appeared earlier in mice drinking normal water only than in mice drinking PJ (8 days vs. 11-14 days). Moreover, tumor growth rates were significantly reduced in mice drinking PJ compared with mice drinking normal water only. Animals drinking PJ also exhibited significant reductions in <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044088/" class="def">serum</a> PSA levels compared with animals drinking normal water only.[<a class="bk_pop" href="#CDR0000719335_rl_162_14">14</a>] In other studies, treatment with a POMx resulted in decreased tumor volumes in SCID mice that had been injected with prostate cancer cells.[<a class="bk_pop" href="#CDR0000719335_rl_162_8">8</a>,<a class="bk_pop" href="#CDR0000719335_rl_162_17">17</a>]</p><p id="CDR0000719335__97">Similarly, when nude mice were injected with pomegranate seed oil (2 µg/g body weight), pomegranate pericarp (peel) polyphenols (2 µg/g body weight), or <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046152/" class="def">saline</a> 5 to 10 minutes prior to being implanted with solid prostate cancer tumors, mice injected with the pomegranate extracts had significantly smaller tumor volumes compared with the mice injected with saline (<i>P</i> < .001).[<a class="bk_pop" href="#CDR0000719335_rl_162_9">9</a>]</p><p id="CDR0000719335__98">In a study reported in 2011, 6-week-old <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000691466/" class="def">transgenic</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046216/" class="def">adenocarcinoma</a> of the mouse prostate (TRAMP) mice received normal drinking water or PJ (0.1% or 0.2% POMx in drinking water) for 28 weeks. The results showed that 100% of the mice that received water only developed tumors by age 20 weeks, whereas just 30% and 20% of the mice that received 0.1% and 0.2% PJ, respectively, developed tumors. By age 34 weeks, 90% of the water-fed mice exhibited metastases to distant organs whereas only 20% of the mice that received pomegranate juice showed metastasis. The PJ-supplemented mice exhibited significantly increased life spans compared with the water-fed mice.<div class="milestone-end"></div>[<a class="bk_pop" href="#CDR0000719335_rl_162_18">18</a>]</p></div></div><div id="CDR0000719335__99"><h3>Human Studies</h3><p id="CDR0000719335__100">Three clinical studies have examined the effect of interventions with pomegranate products on changes in PSADT in patients with biochemically recurrent prostate cancer who had a rising PSA after <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045570/" class="def">surgery</a> or <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044971/" class="def">radiation therapy</a> for presumed localized cancer. The first study was a single-arm trial of 48 patients who drank 8 ounces (570 mg/d total polyphenol gallic acid equivalents) of PJ for up to 33 months. PSADT rose from a mean of 15 months (±11 months) at baseline to a mean of 54 months (±102 months, <i>P</i> < .001) on treatment (with a twofold increase in median PSADT from 11.8 to 24 months, <i>P</i> = .029).[<a class="bk_pop" href="#CDR0000719335_rl_162_19">19</a>]</p><p id="CDR0000719335__253">The second phase II study was published in 2013 and randomly assigned 92 patients to either 1 g (polyphenol gallic acid content equivalent to 8 ounces of pomegranate juice [47 patients]) or 3 g (45 patients) of pomegranate extract powder for up to 18 months. Overall, median PSADT increased from 11.9 to 18.5 months (<i>P</i> < .001), but no dose effect was seen (<i>P</i> = .554). Median PSADT increased from 11.9 to 18.8 months in the low-dose arm and from 12.2 to 17.5 months in the high-dose arm.[<a class="bk_pop" href="#CDR0000719335_rl_162_20">20</a>]</p><p id="CDR0000719335__634">The third trial was a randomized, double-blinded, placebo controlled study published in 2015. Of the 183 patients who enrolled, 64 patients were treated with placebo, 17 patients were treated with PJ, and 102 patients were treated with pomegranate liquid extract, which contained the same compounds found in PJ, with the exception of a higher proportional content of pomegranate polyphenol and a lower anthocyanadin content. The median change in PSADT was 4.5 months for the placebo group, 1.6 months for the extract group, and 7.6 months for the juice group; however, no paired comparison of groups was statistically significant.[<a class="bk_pop" href="#CDR0000719335_rl_162_21">21</a>]</p><p id="CDR0000719335__635">The differences in results between the trials may be partly because of less aggressive disease in the 2006 patient population with lower starting PSA values but may also be because the first two trials lacked a placebo arm. All three trials found that pomegranate extract was safe to consume. Of note, in both the 2006 and 2013 studies, two patients in each trial had a 50% decline in PSA. In light of these findings, researchers wondered if there may be a sensitive subpopulation who would benefit from PJ. One potential genetic biomarker candidate is manganese superoxide dismutase (MnSOD), which is the primary antioxidant enzyme in <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044060/" class="def">mitochondria</a>. A <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000044805/" class="def">polymorphism</a> at codon 16 of the MnSOD gene in men encodes either alanine (A) or valine (V). The AA genotype has been associated with more aggressive prostate cancer and with more sensitivity to antioxidants than the VA or VV genotype.[<a class="bk_pop" href="#CDR0000719335_rl_162_22">22</a>] A preplanned subset analysis in the 2015 study of the 34 (22%) men with MnSOD AA genotype demonstrated a greater PSADT lengthening in the liquid extract group (median PSADT increased from 13.6 months to 25.6 months, <i>P</i> = .03) while no significant change was seen in the placebo group of MnSOD (median PSADT increased from 10.9–12.7 months, <i>P</i> = .22). In summary, the finding that men with the AA genotype who received pomegranate extract had greater lengthening of PSADT than did men in the placebo arm, along with the safe profile of PJ and extract in three large studies, suggest that there may be benefit in further studies in the AA MnSOD subpopulation.</p><div id="CDR0000719335__167"><h4>Current clinical trials</h4><p id="CDR0000719335__168">Check NCI’s list of cancer clinical trials for CAM clinical trials on <a href="https://www.cancer.gov/about-cancer/treatment/clinical-trials/search/results?protocolsearchid=10188053&vers=1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">pomegranate-extract pill for prostate cancer</a>, <a href="https://www.cancer.gov/about-cancer/treatment/clinical-trials/search/results?protocolsearchid=12081398&vers=1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">pomegranate juice for prostate cancer</a>, and <a href="https://www.cancer.gov/about-cancer/treatment/clinical-trials/search/results?protocolsearchid=10202262&vers=1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">pomegranate liquid extract for prostate cancer</a> that are actively enrolling patients.</p><p id="CDR0000719335__169">General information about clinical trials is also available from the <a href="https://www.cancer.gov/about-cancer/treatment/clinical-trials" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NCI website</a>.</p></div></div><div id="CDR0000719335__144"><h3>Adverse Effects</h3><p id="CDR0000719335__145">In a study of prostate cancer patients reported in 2006, the PJ intervention was well tolerated and no serious adverse effects were observed.[<a class="bk_pop" href="#CDR0000719335_rl_162_19">19</a>]</p><p id="CDR0000719335__146">In a <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045838/" class="def">pilot study</a> reported in 2007, the safety of PJ in patients with <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000321372/" class="def">erectile dysfunction</a> was examined. No serious adverse effects were observed during this study, and no participant dropped out due to adverse <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046580/" class="def">side effects</a>. In the <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000390238/" class="def">analysis</a> of the results, no statistical comparisons were made of the adverse side effects observed in the intervention arm and the <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046688/" class="def">placebo</a> arm.[<a class="bk_pop" href="#CDR0000719335_rl_162_23">23</a>]</p></div><div id="CDR0000719335_rl_162"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000719335_rl_162_1">Jurenka JS: Therapeutic applications of pomegranate (Punica granatum L.): a review. Altern Med Rev 13 (2): 128-44, 2008. [<a href="https://pubmed.ncbi.nlm.nih.gov/18590349" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18590349</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_162_2">Langley P: Why a pomegranate? BMJ 321 (7269): 1153-4, 2000. [<a href="/pmc/articles/PMC1118911/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1118911</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/11061746" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11061746</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_162_3">Viuda-Martos M, Fernandez-Lopez J, Perez-Alvarez JA: Pomegranate and its many functional components as related to human health: a review. Compr Rev Food Sci Food Saf 9 (6): 635-54, 2010. <a href="http://onlinelibrary.wiley.com/doi/10.1111/j.1541-4337.2010.00131.x/pdf" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">Available online</a>. Last accessed April 7, 2017. [<a href="https://pubmed.ncbi.nlm.nih.gov/33467822" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 33467822</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_162_4">Basu A, Penugonda K: Pomegranate juice: a heart-healthy fruit juice. Nutr Rev 67 (1): 49-56, 2009. [<a href="https://pubmed.ncbi.nlm.nih.gov/19146506" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19146506</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_162_5">Yuan T, Ma H, Liu W, et al.: Pomegranate's Neuroprotective Effects against Alzheimer's Disease Are Mediated by Urolithins, Its Ellagitannin-Gut Microbial Derived Metabolites. ACS Chem Neurosci 7 (1): 26-33, 2016. [<a href="https://pubmed.ncbi.nlm.nih.gov/26559394" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26559394</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_162_6">Aviram M, Rosenblat M, Gaitini D, et al.: Pomegranate juice consumption for 3 years by patients with carotid artery stenosis reduces common carotid intima-media thickness, blood pressure and LDL oxidation. Clin Nutr 23 (3): 423-33, 2004. [<a href="https://pubmed.ncbi.nlm.nih.gov/15158307" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15158307</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_162_7">Menezes SM, Cordeiro LN, Viana GS: Punica granatum (pomegranate) extract is active against dental plaque. J Herb Pharmacother 6 (2): 79-92, 2006. [<a href="https://pubmed.ncbi.nlm.nih.gov/17182487" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17182487</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_162_8">Seeram NP, Aronson WJ, Zhang Y, et al.: Pomegranate ellagitannin-derived metabolites inhibit prostate cancer growth and localize to the mouse prostate gland. J Agric Food Chem 55 (19): 7732-7, 2007. [<a href="https://pubmed.ncbi.nlm.nih.gov/17722872" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17722872</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_162_9">Albrecht M, Jiang W, Kumi-Diaka J, et al.: Pomegranate extracts potently suppress proliferation, xenograft growth, and invasion of human prostate cancer cells. J Med Food 7 (3): 274-83, 2004. [<a href="https://pubmed.ncbi.nlm.nih.gov/15383219" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15383219</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_162_10">Gasmi J, Sanderson JT: Growth inhibitory, antiandrogenic, and pro-apoptotic effects of punicic acid in LNCaP human prostate cancer cells. J Agric Food Chem 58 (23): 12149-56, 2010. [<a href="https://pubmed.ncbi.nlm.nih.gov/21067181" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21067181</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_162_11">Hong MY, Seeram NP, Heber D: Pomegranate polyphenols down-regulate expression of androgen-synthesizing genes in human prostate cancer cells overexpressing the androgen receptor. J Nutr Biochem 19 (12): 848-55, 2008. [<a href="/pmc/articles/PMC2610864/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2610864</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/18479901" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18479901</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_162_12">Lansky EP, Jiang W, Mo H, et al.: Possible synergistic prostate cancer suppression by anatomically discrete pomegranate fractions. Invest New Drugs 23 (1): 11-20, 2005. [<a href="https://pubmed.ncbi.nlm.nih.gov/15528976" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15528976</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_162_13">Koyama S, Cobb LJ, Mehta HH, et al.: Pomegranate extract induces apoptosis in human prostate cancer cells by modulation of the IGF-IGFBP axis. Growth Horm IGF Res 20 (1): 55-62, 2010. [<a href="/pmc/articles/PMC2815223/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2815223</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19853487" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19853487</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_162_14">Malik A, Afaq F, Sarfaraz S, et al.: Pomegranate fruit juice for chemoprevention and chemotherapy of prostate cancer. Proc Natl Acad Sci U S A 102 (41): 14813-8, 2005. [<a href="/pmc/articles/PMC1253570/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1253570</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/16192356" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16192356</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_162_15">Kasimsetty SG, Bialonska D, Reddy MK, et al.: Effects of pomegranate chemical constituents/intestinal microbial metabolites on CYP1B1 in 22Rv1 prostate cancer cells. J Agric Food Chem 57 (22): 10636-44, 2009. [<a href="https://pubmed.ncbi.nlm.nih.gov/19919114" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19919114</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_162_16">Wang L, Alcon A, Yuan H, et al.: Cellular and molecular mechanisms of pomegranate juice-induced anti-metastatic effect on prostate cancer cells. Integr Biol (Camb) 3 (7): 742-54, 2011. [<a href="https://pubmed.ncbi.nlm.nih.gov/21594291" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21594291</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_162_17">Sartippour MR, Seeram NP, Rao JY, et al.: Ellagitannin-rich pomegranate extract inhibits angiogenesis in prostate cancer in vitro and in vivo. Int J Oncol 32 (2): 475-80, 2008. [<a href="https://pubmed.ncbi.nlm.nih.gov/18202771" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18202771</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_162_18">Adhami VM, Siddiqui IA, Syed DN, et al.: Oral infusion of pomegranate fruit extract inhibits prostate carcinogenesis in the TRAMP model. Carcinogenesis 33 (3): 644-51, 2012. [<a href="/pmc/articles/PMC3291862/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3291862</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/22198212" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22198212</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_162_19">Pantuck AJ, Leppert JT, Zomorodian N, et al.: Phase II study of pomegranate juice for men with rising prostate-specific antigen following surgery or radiation for prostate cancer. Clin Cancer Res 12 (13): 4018-26, 2006. [<a href="https://pubmed.ncbi.nlm.nih.gov/16818701" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16818701</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_162_20">Paller CJ, Ye X, Wozniak PJ, et al.: A randomized phase II study of pomegranate extract for men with rising PSA following initial therapy for localized prostate cancer. Prostate Cancer Prostatic Dis 16 (1): 50-5, 2013. [<a href="/pmc/articles/PMC3549301/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3549301</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/22689129" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22689129</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_162_21">Pantuck AJ, Pettaway CA, Dreicer R, et al.: A randomized, double-blind, placebo-controlled study of the effects of pomegranate extract on rising PSA levels in men following primary therapy for prostate cancer. Prostate Cancer Prostatic Dis 18 (3): 242-8, 2015. [<a href="https://pubmed.ncbi.nlm.nih.gov/26169045" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26169045</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_162_22">Iguchi T, Wang CY, Delongchamps NB, et al.: Association of MnSOD AA Genotype with the Progression of Prostate Cancer. PLoS One 10 (7): e0131325, 2015. [<a href="/pmc/articles/PMC4492976/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4492976</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/26147925" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26147925</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_162_23">Forest CP, Padma-Nathan H, Liker HR: Efficacy and safety of pomegranate juice on improvement of erectile dysfunction in male patients with mild to moderate erectile dysfunction: a randomized, placebo-controlled, double-blind, crossover study. Int J Impot Res 19 (6): 564-7, 2007 Nov-Dec. [<a href="https://pubmed.ncbi.nlm.nih.gov/17568759" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17568759</span></a>]</div></li></ol></div></div><div id="CDR0000719335__283"><h2 id="_CDR0000719335__283_">Selenium</h2><div id="CDR0000719335__284"><h3>Overview</h3><p id="CDR0000719335__285">This section contains the following key information:</p><ul id="CDR0000719335__286"><li class="half_rhythm"><div><a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045113/" class="def">Selenium</a> is an essential trace <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045787/" class="def">mineral</a> involved in a number of <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044510/" class="def">biological</a> processes, including <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000641114/" class="def">kinase</a> regulation, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000537335/" class="def">gene expression</a>, and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045721/" class="def">immune function</a>.</div></li><li class="half_rhythm"><div><a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000454774/" class="def">Animal</a> and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000257225/" class="def">epidemiological</a> studies have suggested there may be an inverse relationship between selenium <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045916/" class="def">supplementation</a> and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045333/" class="def">cancer</a> risk.</div></li><li class="half_rhythm"><div>The results of epidemiologic studies suggest some complexity in the association between <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000270735/" class="def">blood</a> levels of selenium and the risk of developing <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000445079/" class="def">prostate cancer</a>. </div></li><li class="half_rhythm"><div>The Selenium and Vitamin E Cancer Prevention Trial (SELECT), a large <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044939/" class="def">multicenter</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045961/" class="def">clinical trial</a>, was initiated to examine the effects of selenium and/or <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045023/" class="def">vitamin E</a> on the development of prostate cancer.</div></li><li class="half_rhythm"><div>Initial results of SELECT, published in 2009, showed no <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044167/" class="def">statistically significant</a> difference in the rate of prostate cancer in men who were randomly assigned to receive the selenium supplements.</div></li><li class="half_rhythm"><div>In 2011, updated results from SELECT showed no <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000390271/" class="def">significant</a> effects of selenium supplementation on risk, but men who took vitamin E alone had a 17% increase in prostate cancer risk compared with men who took placebo.</div></li><li class="half_rhythm"><div>In 2014, an analysis of SELECT results showed that men who had high selenium status at <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000467830/" class="def">baseline</a> and who were randomly assigned to receive selenium supplementation had an increased risk of <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000386205/" class="def">high-grade</a> prostate cancer.</div></li></ul></div><div id="CDR0000719335__287"><h3>General Information and History</h3><p id="CDR0000719335__288">Selenium is an essential trace mineral involved in a number of biological processes, including enzyme regulation, gene expression, and immune function. Selenium was discovered in 1818 and named after the Greek goddess of the moon, Selene.[<a class="bk_pop" href="#CDR0000719335_rl_283_1">1</a>] A number of selenoproteins have been identified in humans, including selenoprotein P (SEPP), which is the main selenium carrier in the body and is important for selenium <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000449741/" class="def">homeostasis</a>.</p><p id="CDR0000719335__289"> Food sources of selenium include meat, vegetables, and nuts. The selenium content of the soil where food is raised determines the amount of selenium found in plants and animals. For adults, the recommended daily allowance for selenium is 55 <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000306521/" class="def">µg</a>/d.[<a class="bk_pop" href="#CDR0000719335_rl_283_2">2</a>] Most <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000373932/" class="def">dietary</a> selenium occurs as selenocysteine or selenomethionine.[<a class="bk_pop" href="#CDR0000719335_rl_283_1">1</a>] Selenium accumulates in the <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044751/" class="def">thyroid gland</a>, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046312/" class="def">liver</a>, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046254/" class="def">pancreas</a>, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046229/" class="def">pituitary gland</a>, and renal medulla.[<a class="bk_pop" href="#CDR0000719335_rl_283_3">3</a>]</p><p id="CDR0000719335__290">Selenium is a component of the <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046081/" class="def">enzyme</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000373010/" class="def">glutathione</a> peroxidase, an enzyme that functions as an <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000043997/" class="def">antioxidant</a>.[<a class="bk_pop" href="#CDR0000719335_rl_283_4">4</a>] However, at high <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000683342/" class="def">concentrations</a>, selenium may function as a <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000372940/" class="def">pro-oxidant</a>.[<a class="bk_pop" href="#CDR0000719335_rl_283_2">2</a>]</p><p id="CDR0000719335__291">Selenium is implicated in a number of disease states. Selenium <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000321364/" class="def">deficiency</a> may result in Keshan disease, a form of childhood cardiomyopathy, and Kaskin-Beck disease, a bone <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000407758/" class="def">disorder</a>.[<a class="bk_pop" href="#CDR0000719335_rl_283_5">5</a>] Some clinical trials have suggested that high levels of selenium may be associated with <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044911/" class="def">diabetes</a> [<a class="bk_pop" href="#CDR0000719335_rl_283_6">6</a>] and high <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000407756/" class="def">cholesterol</a>.[<a class="bk_pop" href="#CDR0000719335_rl_283_2">2</a>]</p><p id="CDR0000719335__292">Selenium may also play a role in cancer. Animal and epidemiological studies have suggested there may be an inverse relationship between selenium supplementation and cancer risk.[<a class="bk_pop" href="#CDR0000719335_rl_283_7">7</a>] The Nutritional Prevention of Cancer Trial (NPC) was a <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045858/" class="def">randomized</a>, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044840/" class="def">placebo-controlled</a> study designed to test the <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044209/" class="def">hypothesis</a> that higher selenium levels were associated with lower <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046145/" class="def">incidence</a> of <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000445084/" class="def">skin cancer</a>. The results indicated that selenium supplementation did not affect risk of skin cancer, although incidences of <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000445043/" class="def">lung</a>, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000444983/" class="def">colorectal</a>, and prostate cancer were significantly reduced.[<a class="bk_pop" href="#CDR0000719335_rl_283_8">8</a>]</p><p id="CDR0000719335__293">There is evidence that selenoproteins may be associated with <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046487/" class="def">carcinogenesis</a>. For example, reduced expression of glutathione peroxidase 3 and SEPP have been observed in some <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046634/" class="def">tumors</a>, while increased expression of glutathione peroxidase 2 occurs in colorectal and lung tumors.[<a class="bk_pop" href="#CDR0000719335_rl_283_7">7</a>]</p></div><div id="CDR0000719335__294"><h3>Preclinical/Animal Studies</h3><div id="CDR0000719335__295"><h4><i>In vitro</i> studies</h4><p id="CDR0000719335__296">Different selenium-containing <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000422394/" class="def">compounds</a> have variable effects on prostate cancer <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046476/" class="def">cells</a> as well as normal cells and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046683/" class="def">tissues</a>. Both naturally occurring and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000462950/" class="def">synthetic</a> organic forms of selenium have been shown to decrease the growth and function of prostate cancer cells.[<a class="bk_pop" href="#CDR0000719335_rl_283_9">9</a>] In a 2011 study, prostate cancer cells were treated with various forms of selenium; selenite and methylseleninic <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000642987/" class="def">acid</a> (MSeA) had the greatest <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044020/" class="def">cytotoxic</a> effects.[<a class="bk_pop" href="#CDR0000719335_rl_283_10">10</a>]</p><p id="CDR0000719335__297">Studies have suggested that selenium <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000653131/" class="def">nanoparticles</a> may be less <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000043986/" class="def">toxic</a> to normal tissues than are other selenium compounds. One study investigated the effects of selenium nanoparticles on prostate cancer cells. The treated cells had decreased activity of the <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045592/" class="def">androgen</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044958/" class="def">receptor</a>, which led to <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046524/" class="def">apoptosis</a> and growth inhibition.[<a class="bk_pop" href="#CDR0000719335_rl_283_11">11</a>]</p><div id="CDR0000719335__298"><h5>Sodium selenite</h5><p id="CDR0000719335__299">In a 2010 study, prostate cancer cells treated with <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044731/" class="def">sodium</a> selenite (a natural form of selenium) exhibited increased levels of <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045813/" class="def">p53</a> (a <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046657/" class="def">tumor suppressor</a>). Findings also revealed that p53 may play a key role in selenium-induced apoptosis.[<a class="bk_pop" href="#CDR0000719335_rl_283_12">12</a>]</p><p id="CDR0000719335__300">In a second study, the prostate <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000695994/" class="def">cancer cell line</a> LNCaP was modified to separately <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045812/" class="def">overexpress</a> each of four antioxidant enzymes. Cells from the modified cell line were then treated with sodium selenite. The cells overexpressing manganese superoxide dismutase (MnSOD) were the only ones able to suppress selenite-induced apoptosis. These findings suggest that superoxide production in <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044060/" class="def">mitochondria</a> may be important in selenium-induced apoptosis occurring in prostate cancer cells and that levels of MnSOD in cancer cells may determine the effectiveness of selenium in inhibiting those cells.[<a class="bk_pop" href="#CDR0000719335_rl_283_13">13</a>]</p><p id="CDR0000719335__301">One study treated prostate cancer cells and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046509/" class="def">benign prostatic hyperplasia</a> (BPH) cells with sodium selenite. Growth of LNCaP cells was stimulated by noncytotoxic, low concentrations of sodium selenite; while growth inhibition occurred in PC-3 cells at these concentrations—prompting the authors to suggest that selenium may be beneficial in advanced prostate cancer—selenium supplementation may have <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044922/" class="def">adverse effects</a> in hormone-sensitive prostate cancer.[<a class="bk_pop" href="#CDR0000719335_rl_283_14">14</a>] However, the relevance of these findings to the <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044168/" class="def">clinical</a> setting is unclear. These experiments used selenium concentrations of 1 to 10 µg/<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000655103/" class="def">mL</a>, whereas the average U.S. adult male <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044088/" class="def">serum</a> selenium concentrations are about 0.125 µg/mL,[<a class="bk_pop" href="#CDR0000719335_rl_283_15">15</a>] and prostate tissue concentrations are about 1.5 µg/g.[<a class="bk_pop" href="#CDR0000719335_rl_283_16">16</a>]</p></div></div><div id="CDR0000719335__302"><h4>Animal studies</h4><p id="CDR0000719335__303">A 2012 study investigated whether various forms of selenium (i.e., SeMet and selenium-enriched yeast [Se-yeast]) differentially affect <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045618/" class="def">biomarkers</a> in the prostate. Elderly dogs received nutritionally adequate or supranutritional levels of selenium in the form of SeMet or Se-yeast. Both types of selenium supplementation increased selenium levels in toenails and prostate tissue to a similar degree. The different forms of selenium supplementation showed no significant differences in <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000045671/" class="def">DNA</a> damage, proliferation, or apoptosis in the prostate.[<a class="bk_pop" href="#CDR0000719335_rl_283_17">17</a>]</p><p id="CDR0000719335__304">At least one study has compared these three forms of selenium in <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044579/" class="def">athymic nude mice</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044678/" class="def">injected</a> with human prostate cancer cells and found that MSeA was more effective in inhibiting tumor growth than was SeMet or selenite.[<a class="bk_pop" href="#CDR0000719335_rl_283_18">18</a>] Another study investigated the effect of age on selenium <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045487/" class="def">chemoprevention</a> in mice. Mice were fed selenium-depleted or selenium-containing (at nutritional or supranutritional levels) <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044660/" class="def">diets</a> for 6 months or 4 weeks and were then injected with PC-3 prostate cancer cells. Adult mice that were fed selenium-containing diets exhibited fewer tumors than did adult mice fed selenium-depleted diets. In adult mice, selenium-depleted diets resulted in tumors with more <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044290/" class="def">necrosis</a> and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044042/" class="def">inflammation</a> compared with selenium-containing diets. However, in young mice, tumor development and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000467841/" class="def">histopathology</a> were not affected by dietary selenium.[<a class="bk_pop" href="#CDR0000719335_rl_283_19">19</a>]</p><p id="CDR0000719335__305">The effects of MSeA and methylselenocysteine (MSeC) have also been explored in a transgenic model of <i><a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000638205/" class="def">in situ</a></i> murine prostate cancer development, the TRAMP mouse.[<a class="bk_pop" href="#CDR0000719335_rl_283_20">20</a>] Treatment with MSeA and MSeC resulted in slower <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044078/" class="def">progression</a> of <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044345/" class="def">prostatic intraepithelial neoplasia</a> (PIN) lesions, decreased <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046479/" class="def">cell proliferation</a>, and increased apoptosis compared with treatment with water. MSeA treatment also increased survival time of TRAMP mice. TRAMP mice that received MSeA treatment starting at age 10 weeks exhibited less <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046053/" class="def">aggressive</a> prostate cancer than did mice that started treatment at 16 weeks, suggesting early <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000454757/" class="def">intervention</a> with MSeA may be more effective than later treatment. The same research group later investigated some of the cellular mechanisms responsible for the different effects of MSeA and MSeC. MSeA and MSeC were shown to affect proteins involved in different cellular pathways. MSeA mainly affected proteins related to prostate <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046445/" class="def">differentiation</a>, androgen receptor signaling, protein folding, and endoplasmic reticulum-stress responses, whereas MSeC affected enzymes involved in <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000390310/" class="def">phase II detoxification</a> or cytoprotection.[<a class="bk_pop" href="#CDR0000719335_rl_283_21">21</a>] One study suggested that MSeA may inhibit cell growth and increase apoptosis by inactivating PKC isoenzymes.[<a class="bk_pop" href="#CDR0000719335_rl_283_22">22</a>]</p></div></div><div id="CDR0000719335__307"><h3>Human Studies</h3><div id="CDR0000719335__308"><h4>Epidemiological studies</h4><p id="CDR0000719335__309">The results of <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000257225/" class="def">epidemiological</a> studies suggest some complexity in the association between the blood levels of selenium and the risk of acquiring prostate cancer. As part of the European Prospective Investigation into Cancer and Nutrition (EPIC)-Heidelberg study, men completed dietary questionnaires, had blood samples taken, and were monitored every 2 to 3 years for up to 10 years. The findings revealed a significantly decreased risk of prostate cancer for individuals with higher blood selenium concentrations.[<a class="bk_pop" href="#CDR0000719335_rl_283_23">23</a>] In a <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044079/" class="def">prospective</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045838/" class="def">pilot study</a>, prostate cancer patients had significantly lower whole blood selenium levels than did healthy males.[<a class="bk_pop" href="#CDR0000719335_rl_283_24">24</a>] However, in a 2009 study of prostate cancer patients, men with higher <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045839/" class="def">plasma</a> selenium levels were at greater risk of being <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046450/" class="def">diagnosed</a> with aggressive prostate cancer.[<a class="bk_pop" href="#CDR0000719335_rl_283_25">25</a>]</p><p id="CDR0000719335__310">Various molecular pathways have been explored to better understand the association between blood selenium levels and the development of prostate cancer. In the EPIC-Heidelberg study, <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000044805/" class="def">polymorphisms</a> in the selenium-containing enzymes GPX1 and SEP15 <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000045693/" class="def">genes</a> were found to be associated with prostate cancer risk.[<a class="bk_pop" href="#CDR0000719335_rl_283_23">23</a>] Another study that used DNA samples obtained from the EPIC-Heidelberg study suggested that prostate cancer risk may be associated with <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000458046/" class="def">single nucleotide polymorphisms</a> (SNPs) in thioredoxin reductase and selenoprotein K genes along with selenium status.[<a class="bk_pop" href="#CDR0000719335_rl_283_26">26</a>] A 2012 study investigated associations between variants in selenoenzyme genes and risk of prostate cancer and prostate cancer–specific <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000496502/" class="def">mortality</a>. Among SNPs analyzed, only GPX1 <a href="/snp/?term=3448" class="bk_tag" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=snp">rs3448</a> was related to overall prostate cancer risk.[<a class="bk_pop" href="#CDR0000719335_rl_283_27">27</a>]</p><p id="CDR0000719335__311">A <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044120/" class="def">retrospective</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000390238/" class="def">analysis</a> of prostate cancer patients and healthy controls showed an association between aggressive prostate cancer and decreased selenium and SEPP status.[<a class="bk_pop" href="#CDR0000719335_rl_283_28">28</a>] In the Physicians' Health Study, links between SNPs in the SEPP gene (<i>SEPP1</i>) and prostate cancer risk and survival were examined. Two SNPs were significantly associated with prostate cancer incidence: <a href="/snp/?term=11959466" class="bk_tag" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=snp">rs11959466</a> was associated with increased risk, and <a href="/snp/?term=13168440" class="bk_tag" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=snp">rs13168440</a> was associated with decreased risk. Tumor SEPP1 <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000662001/" class="def">mRNA</a> expression levels were lower in men with lethal prostate cancer than in men with nonlethal prostate cancer.[<a class="bk_pop" href="#CDR0000719335_rl_283_29">29</a>] In one study, the direction of the association between blood selenium levels and advanced prostate cancer incidence differed according to which of two polymorphisms a patient had for the gene encoding the enzyme MnSOD. For men with the alanine-alanine (AA) <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000660739/" class="def">genotype</a>, higher selenium levels were associated with a reduced risk of presenting with aggressive disease, whereas the opposite was seen among men with a valine (V) <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000339337/" class="def">allele</a>.[<a class="bk_pop" href="#CDR0000719335_rl_283_25">25</a>]</p><p id="CDR0000719335__547">An analysis of 4,459 men in the Health Professionals Follow-Up Study who were initially diagnosed with prostate cancer found that selenium supplementation of 140 μg or more per day after <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046450/" class="def">diagnosis</a> of <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045805/" class="def">nonmetastatic</a> prostate cancer may increase risk of prostate cancer mortality. The authors recommended caution in the use of selenium supplements among men with prostate cancer. Risk of prostate cancer mortality rose at all levels of selenium consumption. Men who consumed 1 to 24 μg/day, 25 to 139 μg/day, and 140 μg/day or more of supplemental selenium had a 1.18-fold (95% confidence interval [CI], 0.73–1.91), 1.33-fold (95% CI, 0.77–2.30), and 2.60-fold (95% CI, 1.44–4.70) increased prostate cancer mortality risk compared with nonusers, respectively (<i>P</i><sub>trend</sub> = .001). The authors reported no statistically significant association between selenium supplement use and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000543628/" class="def">biochemical recurrence</a>, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000748137/" class="def">cardiovascular disease</a> mortality, or overall mortality.[<a class="bk_pop" href="#CDR0000719335_rl_283_30">30</a>]</p></div><div id="CDR0000719335__312"><h4>Intervention studies</h4><p id="CDR0000719335__315">Sixty adult males were randomly assigned to receive either a daily <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046688/" class="def">placebo</a> or 200 µg of selenium glycinate supplements for 6 weeks. Blood samples were collected at the start and end of the study. Compared with the placebo group, men who received selenium supplements exhibited significantly increased activity of two blood selenium enzymes and significantly decreased levels of <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046540/" class="def">prostate-specific antigen</a> (PSA) at the end of the study.[<a class="bk_pop" href="#CDR0000719335_rl_283_31">31</a>]</p><p id="CDR0000719335__316">A <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000691484/" class="def">meta-analysis</a> published in 2012 reviewed human studies that investigated links between selenium intake, selenium status, and prostate cancer risk. The results suggested an association between decreased prostate cancer risk and a narrow range of selenium status (plasma selenium concentrations up to 170 ng/mL and toenail selenium concentrations between 0.85 and 0.94 µg/g).[<a class="bk_pop" href="#CDR0000719335_rl_283_32">32</a>]</p><p id="CDR0000719335__317">In another study, prostate cancer patients were randomly assigned to receive either combination <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000340936/" class="def">silymarin</a> (570 <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044213/" class="def">mg</a>) and selenomethionine (240 µg) supplement or placebo daily for 6 months following radical prostatectomy. While there was no change in PSA levels between the groups after 6 months, the participants receiving supplements reported improved <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045417/" class="def">quality of life</a> and showed decreases in low-density lipoprotein cholesterol and total cholesterol.[<a class="bk_pop" href="#CDR0000719335_rl_283_33">33</a>]</p><p id="CDR0000719335__413">In one study, 140 prostate cancer patients undergoing <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000616060/" class="def">active surveillance</a> were randomly assigned to receive low-dose selenium (200 µg/d), high-dose selenium (800 µg/d), or placebo daily for up to 5 years. Selenium was given in the form of Se-yeast. Men receiving the high-dose selenium, and who had the highest baseline plasma selenium levels, had a higher <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000651206/" class="def">PSA velocity</a> than did men in the placebo group. There was not a significant effect of selenium supplements on PSA velocity in men who had lower baseline levels of selenium.[<a class="bk_pop" href="#CDR0000719335_rl_283_34">34</a>]</p><p id="CDR0000719335__414">In 2013, results of a phase III randomized, placebo-controlled trial investigating the effect of selenium supplementation on prostate cancer incidence in men at high risk for the disease were reported. Subjects (N = 699) were randomly assigned to receive either daily placebo or one of two doses of high–Se-yeast (200 µg/d or 400 µg/d). They were monitored every 6 months, up to 5 years. Compared with placebo, selenium supplementation had no effect on prostate cancer incidence or PSA velocity.[<a class="bk_pop" href="#CDR0000719335_rl_283_35">35</a>] In an earlier study, men with HGPIN were randomly assigned to receive either placebo or 200 µg of selenium daily for 3 years or until prostate cancer diagnosis. The results suggested that selenium supplementation had no effect on prostate cancer risk.[<a class="bk_pop" href="#CDR0000719335_rl_283_36">36</a>]</p><div id="CDR0000719335__318"><h5>The Selenium and Vitamin E Cancer Prevention Trial (SELECT)</h5><p id="CDR0000719335__319">On the basis of findings from earlier studies,[<a class="bk_pop" href="#CDR0000719335_rl_283_8">8</a>,<a class="bk_pop" href="#CDR0000719335_rl_283_37">37</a>] the SELECT, a large multicenter clinical trial, was initiated by the <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044268/" class="def">National Institutes of Health</a> in 2001 to examine the effects of selenium and/or vitamin E on the development of prostate cancer. SELECT was a <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045833/" class="def">phase III</a>, randomized, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045673/" class="def">double-blind</a>, placebo-controlled, population-based trial.[<a class="bk_pop" href="#CDR0000719335_rl_283_38">38</a>] More than 35,000 men, aged 50 years or older, from more than 400 study sites in the United States, Canada, and Puerto Rico, were randomly assigned to receive vitamin E (<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000691423/" class="def">alpha-tocopherol</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000655020/" class="def">acetate</a>, 400 <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044764/" class="def">IU</a> daily) and a placebo, selenium (L-selenomethionine, 200 µg daily) and a placebo, vitamin E and selenium, or two placebos daily for 7 to 12 years. The <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044163/" class="def">primary endpoint</a> of the clinical trial was incidence of prostate cancer.[<a class="bk_pop" href="#CDR0000719335_rl_283_38">38</a>]</p><p id="CDR0000719335__320">Initial results of SELECT were published in 2009. There were no statistically significant differences in rates of prostate cancer in the four groups. In the vitamin E–alone group, there was a nonsignificant increase in rates of prostate cancer (<i>P</i> = .06); in the selenium–alone group, there was a nonsignificant increase in incidence of <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044129/" class="def">diabetes mellitus</a> (<i>P</i> = .16). On the basis of those findings, the data and safety monitoring committee recommended that participants stop taking the study supplements.[<a class="bk_pop" href="#CDR0000719335_rl_283_39">39</a>]</p><p id="CDR0000719335__321">Updated results were published in 2011. When compared with the placebo group, the rate of prostate cancer detection was significantly greater in the vitamin E–alone group (<i>P</i> = .008) and represented a 17% increase in prostate cancer risk. There was also greater incidence of prostate cancer in men who had taken selenium than in men who took placebo, but those differences were not statistically significant.[<a class="bk_pop" href="#CDR0000719335_rl_283_40">40</a>]</p><p id="CDR0000719335__322">A number of explanations have been suggested, including the dose and form of vitamin E that was used in the trial as well as the specific form of selenium chosen for the study. L-selenomethionine was used in SELECT, while selenite and Se-yeast had been used in previous studies. SELECT researchers chose selenomethionine because it was the major component of Se-yeast and because selenite was not absorbed well by the body, resulting in lower selenium stores.[<a class="bk_pop" href="#CDR0000719335_rl_283_41">41</a>] In addition, there were concerns about product consistency with high–Se-yeast.[<a class="bk_pop" href="#CDR0000719335_rl_283_42">42</a>] However, selenomethionine is involved in general protein synthesis and can have numerous metabolites such as methylselenol, which may have <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000446109/" class="def">antitumor</a> properties.[<a class="bk_pop" href="#CDR0000719335_rl_283_43">43</a>,<a class="bk_pop" href="#CDR0000719335_rl_283_44">44</a>]</p><p id="CDR0000719335__463">Toenail selenium concentrations were examined in two-case cohort subset studies of SELECT participants. Total selenium concentration in the absence of supplementation was not associated with prostate cancer risk. Selenium supplementation in SELECT had no effect on prostate cancer risk among men with low selenium status at baseline but increased the risk of high-grade prostate cancer in men with higher baseline selenium status by 91% (<i>P</i> = .007). The authors concluded that men should avoid selenium supplementation at doses exceeding recommended dietary intakes.[<a class="bk_pop" href="#CDR0000719335_rl_283_45">45</a>] An international collaboration compiled and reanalyzed data from 15 studies that investigated the association between blood and toenail selenium concentrations and prostate cancer risk.[<a class="bk_pop" href="#CDR0000719335_rl_283_46">46</a>] In the analysis of 6,497 men with prostate cancer and 8,107 controls, blood selenium level was not associated with the risk of total prostate cancer, but high blood selenium level was associated with a lower risk of aggressive disease. Toenail selenium concentration was inversely associated with risk of total prostate cancer (<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000618610/" class="def">odds ratio</a>, 0.29; 95% CI, 0.22–0.40; <i>P</i><sub>trend</sub> < .001), including both aggressive and nonaggressive disease. </p><p id="CDR0000719335__621">In a case-cohort analysis of 1,434 men in the SELECT who underwent analysis of SNPs in 21 genes, investigators found support for the hypothesis that genetic variation in selenium and vitamin E metabolism/transport genes may influence the risk of overall and high-grade prostate cancer and that selenium or vitamin E supplementation may modify an individual's response to those risks.[<a class="bk_pop" href="#CDR0000719335_rl_283_47">47</a>]</p></div></div><div id="CDR0000719335__326"><h4>Current clinical trials</h4><p id="CDR0000719335__327">Check NCI’s list of cancer clinical trials for CAM clinical trials on <a href="https://www.cancer.gov/about-cancer/treatment/clinical-trials/search/results?protocolsearchid=12112361&vers=1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">selenium</a> that are actively enrolling patients.</p><p id="CDR0000719335__406">General information about clinical trials is also available from the <a href="https://www.cancer.gov/about-cancer/treatment/clinical-trials" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NCI website</a>.</p></div></div><div id="CDR0000719335__324"><h3>Adverse Effects</h3><p id="CDR0000719335__325">Selenium supplementation was well tolerated in many clinical trials. In two published trials, there were no differences reported in adverse effects between placebo or treatment groups.[<a class="bk_pop" href="#CDR0000719335_rl_283_34">34</a>,<a class="bk_pop" href="#CDR0000719335_rl_283_35">35</a>] However, in SELECT, selenium supplementation was associated with a nonsignificant increase in incidence of diabetes mellitus (<i>P</i> = .08).[<a class="bk_pop" href="#CDR0000719335_rl_283_39">39</a>]</p></div><div id="CDR0000719335_rl_283"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000719335_rl_283_1">Brown KM, Arthur JR: Selenium, selenoproteins and human health: a review. Public Health Nutr 4 (2B): 593-9, 2001. 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[<a href="/pmc/articles/PMC2822708/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2822708</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19401524" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19401524</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_283_21">Zhang J, Wang L, Anderson LB, et al.: Proteomic profiling of potential molecular targets of methyl-selenium compounds in the transgenic adenocarcinoma of mouse prostate model. Cancer Prev Res (Phila) 3 (8): 994-1006, 2010. 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[<a href="/pmc/articles/PMC3259896/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3259896</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/18922790" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18922790</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_283_23">Steinbrecher A, Méplan C, Hesketh J, et al.: Effects of selenium status and polymorphisms in selenoprotein genes on prostate cancer risk in a prospective study of European men. Cancer Epidemiol Biomarkers Prev 19 (11): 2958-68, 2010. 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[<a href="/pmc/articles/PMC3486803/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3486803</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/23133653" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23133653</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_283_27">Geybels MS, Hutter CM, Kwon EM, et al.: Variation in selenoenzyme genes and prostate cancer risk and survival. Prostate 73 (7): 734-42, 2013. [<a href="/pmc/articles/PMC3859305/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3859305</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/23143801" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23143801</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_283_28">Meyer HA, Hollenbach B, Stephan C, et al.: Reduced serum selenoprotein P concentrations in German prostate cancer patients. Cancer Epidemiol Biomarkers Prev 18 (9): 2386-90, 2009. [<a href="https://pubmed.ncbi.nlm.nih.gov/19690186" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19690186</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_283_29">Penney KL, Li H, Mucci LA, et al.: Selenoprotein P genetic variants and mrna expression, circulating selenium, and prostate cancer risk and survival. Prostate 73 (7): 700-5, 2013. [<a href="/pmc/articles/PMC3640488/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3640488</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/23129481" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23129481</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_283_30">Kenfield SA, Van Blarigan EL, DuPre N, et al.: Selenium supplementation and prostate cancer mortality. J Natl Cancer Inst 107 (1): 360, 2015. [<a href="/pmc/articles/PMC4296194/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4296194</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/25505227" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25505227</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_283_31">Zhang W, Joseph E, Hitchcock C, et al.: Selenium glycinate supplementation increases blood glutathione peroxidase activities and decreases prostate-specific antigen readings in middle-aged US men. Nutr Res 31 (2): 165-8, 2011. [<a href="https://pubmed.ncbi.nlm.nih.gov/21419321" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21419321</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_283_32">Hurst R, Hooper L, Norat T, et al.: Selenium and prostate cancer: systematic review and meta-analysis. Am J Clin Nutr 96 (1): 111-22, 2012. [<a href="https://pubmed.ncbi.nlm.nih.gov/22648711" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22648711</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_283_33">Vidlar A, Vostalova J, Ulrichova J, et al.: The safety and efficacy of a silymarin and selenium combination in men after radical prostatectomy - a six month placebo-controlled double-blind clinical trial. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 154 (3): 239-44, 2010. [<a href="https://pubmed.ncbi.nlm.nih.gov/21048810" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21048810</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_283_34">Stratton MS, Algotar AM, Ranger-Moore J, et al.: Oral selenium supplementation has no effect on prostate-specific antigen velocity in men undergoing active surveillance for localized prostate cancer. Cancer Prev Res (Phila) 3 (8): 1035-43, 2010. [<a href="/pmc/articles/PMC4533875/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4533875</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/20647337" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20647337</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_283_35">Algotar AM, Stratton MS, Ahmann FR, et al.: Phase 3 clinical trial investigating the effect of selenium supplementation in men at high-risk for prostate cancer. Prostate 73 (3): 328-35, 2013. [<a href="/pmc/articles/PMC4086804/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4086804</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/22887343" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22887343</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_283_36">Marshall JR, Tangen CM, Sakr WA, et al.: Phase III trial of selenium to prevent prostate cancer in men with high-grade prostatic intraepithelial neoplasia: SWOG S9917. Cancer Prev Res (Phila) 4 (11): 1761-9, 2011. [<a href="/pmc/articles/PMC3208719/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3208719</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/21896650" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21896650</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_283_37">The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. N Engl J Med 330 (15): 1029-35, 1994. [<a href="https://pubmed.ncbi.nlm.nih.gov/8127329" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8127329</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_283_38">Klein EA: Selenium and vitamin E cancer prevention trial. Ann N Y Acad Sci 1031: 234-41, 2004. [<a href="https://pubmed.ncbi.nlm.nih.gov/15753149" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15753149</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_283_39">Lippman SM, Klein EA, Goodman PJ, et al.: Effect of selenium and vitamin E on risk of prostate cancer and other cancers: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA 301 (1): 39-51, 2009. [<a href="/pmc/articles/PMC3682779/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3682779</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19066370" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19066370</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_283_40">Klein EA, Thompson IM Jr, Tangen CM, et al.: Vitamin E and the risk of prostate cancer: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA 306 (14): 1549-56, 2011. [<a href="/pmc/articles/PMC4169010/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4169010</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/21990298" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21990298</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_283_41">Lippman SM, Goodman PJ, Klein EA, et al.: Designing the Selenium and Vitamin E Cancer Prevention Trial (SELECT). J Natl Cancer Inst 97 (2): 94-102, 2005. [<a href="https://pubmed.ncbi.nlm.nih.gov/15657339" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15657339</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_283_42">Ledesma MC, Jung-Hynes B, Schmit TL, et al.: Selenium and vitamin E for prostate cancer: post-SELECT (Selenium and Vitamin E Cancer Prevention Trial) status. Mol Med 17 (1-2): 134-43, 2011 Jan-Feb. [<a href="/pmc/articles/PMC3022975/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3022975</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/20882260" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20882260</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_283_43">Hatfield DL, Gladyshev VN: The Outcome of Selenium and Vitamin E Cancer Prevention Trial (SELECT) reveals the need for better understanding of selenium biology. Mol Interv 9 (1): 18-21, 2009. [<a href="/pmc/articles/PMC2718722/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2718722</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19299660" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19299660</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_283_44">Ohta Y, Kobayashi Y, Konishi S, et al.: Speciation analysis of selenium metabolites in urine and breath by HPLC- and GC-inductively coupled plasma-MS after administration of selenomethionine and methylselenocysteine to rats. Chem Res Toxicol 22 (11): 1795-801, 2009. [<a href="https://pubmed.ncbi.nlm.nih.gov/19715347" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19715347</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_283_45">Kristal AR, Darke AK, Morris JS, et al.: Baseline selenium status and effects of selenium and vitamin e supplementation on prostate cancer risk. J Natl Cancer Inst 106 (3): djt456, 2014. [<a href="/pmc/articles/PMC3975165/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3975165</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/24563519" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24563519</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_283_46">Allen NE, Travis RC, Appleby PN, et al.: Selenium and Prostate Cancer: Analysis of Individual Participant Data From Fifteen Prospective Studies. J Natl Cancer Inst 108 (11): , 2016. [<a href="/pmc/articles/PMC5241899/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5241899</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/27385803" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 27385803</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_283_47">Chan JM, Darke AK, Penney KL, et al.: Selenium- or Vitamin E-Related Gene Variants, Interaction with Supplementation, and Risk of High-Grade Prostate Cancer in SELECT. Cancer Epidemiol Biomarkers Prev 25 (7): 1050-8, 2016. [<a href="/pmc/articles/PMC5086806/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5086806</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/27197287" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 27197287</span></a>]</div></li></ol></div></div><div id="CDR0000719335__163"><h2 id="_CDR0000719335__163_">Soy</h2><div id="CDR0000719335__102"><h3>Overview</h3><p id="CDR0000719335__103">This section contains the following key information:</p><ul id="CDR0000719335__104"><li class="half_rhythm"><div><a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000407766/" class="def">Soy</a> foods (e.g., soy milk, miso, tofu, and soy flour) contain <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044709/" class="def">phytochemicals</a> that may have health benefits and, among these, soy <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046660/" class="def">isoflavones</a> have been the focus of most of the research.</div></li><li class="half_rhythm"><div>Soy isoflavones are <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000330175/" class="def">phytoestrogens</a>. The major isoflavones in <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000415913/" class="def">soybeans</a> are <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046107/" class="def">genistein</a> (the most abundant), <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000285740/" class="def">daidzein</a>, and glycitein.</div></li><li class="half_rhythm"><div>Genistein affects components of multiple growth and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044572/" class="def">proliferation</a>-related pathways in <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000445079/" class="def">prostate cancer</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046476/" class="def">cells</a>, including the <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000589403/" class="def">COX-2</a>/<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000559143/" class="def">prostaglandin</a>, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000653114/" class="def">epidermal growth factor</a> (EGF), and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000653119/" class="def">insulin-like growth factor</a> (IGF) pathways.</div></li><li class="half_rhythm"><div>Some <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044517/" class="def">preclinical studies</a> have indicated that the combined effect of multiple isoflavones may be greater than that of a single isoflavone.</div></li><li class="half_rhythm"><div>Some <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000454774/" class="def">animal studies</a> have demonstrated prostate cancer <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000439419/" class="def">prevention</a> effects with soy and genistein; however, other animal studies have yielded conflicting results regarding beneficial effects of genistein on prostate cancer <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046710/" class="def">metastasis</a>.</div></li><li class="half_rhythm"><div><a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000257225/" class="def">Epidemiologic</a> studies have generally found high consumption of nonfermented soy foods to be associated with a decreased risk of prostate cancer. </div></li><li class="half_rhythm"><div>Limited human prevention studies have been conducted, and, so far, they have not yielded consistent or definitive findings.</div></li><li class="half_rhythm"><div>Treatment trials of various <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044664/" class="def">doses</a> and preparations of soy isoflavones in men with prostate cancer have yielded varying results but have generally failed to demonstrate significant effects on <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046540/" class="def">prostate-specific antigen</a> (PSA) levels.</div></li><li class="half_rhythm"><div>A few <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045961/" class="def">clinical trials</a> of soy <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046092/" class="def">protein</a> or whole soy products have provided preliminary evidence of the ability of these products to lower PSA levels in men with prostate cancer.</div></li><li class="half_rhythm"><div>Soy products are generally well tolerated in patients with prostate cancer. In clinical trials, the most commonly reported <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046580/" class="def">side effects</a> were mild <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045692/" class="def">gastrointestinal</a> symptoms.</div></li></ul></div><div id="CDR0000719335__105"><h3>General Information & History</h3><p id="CDR0000719335__106">Although records of soy use in China date back to the eleventh century BC, it was not until the 18th century that the plant reached Europe and the United States. The soybean is an incredibly versatile plant: it can be processed into a variety of products including soy milk, miso, tofu, soy flour, and soy oil.[<a class="bk_pop" href="#CDR0000719335_rl_163_1">1</a>]</p><p id="CDR0000719335__107">Soy foods contain a number of phytochemicals that may have health benefits but isoflavones have garnered the most attention. Among the isoflavones found in soybeans, genistein is the most abundant and may have the most <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044510/" class="def">biological</a> activity.[<a class="bk_pop" href="#CDR0000719335_rl_163_2">2</a>] Other isoflavones found in soy include daidzein and glycitein.[<a class="bk_pop" href="#CDR0000719335_rl_163_3">3</a>] Isoflavones help soybeans survive in times of <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000450122/" class="def">stress</a> and have <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000043997/" class="def">antioxidant</a>, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000462661/" class="def">antimicrobial</a>, and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046085/" class="def">antifungal</a> properties.[<a class="bk_pop" href="#CDR0000719335_rl_163_4">4</a>]</p><p id="CDR0000719335__108">Isoflavones are quickly taken up by the gut and can be detected in <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045839/" class="def">plasma</a> as soon as 30 minutes after the consumption of soy products. Studies suggest that maximum levels of isoflavone plasma <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000683342/" class="def">concentration</a> may be achieved by 6 hours following soy product consumption.[<a class="bk_pop" href="#CDR0000719335_rl_163_5">5</a>] Isoflavones are phytoestrogens (they bind to <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046409/" class="def">estrogen receptors</a>) with a greater binding <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000655052/" class="def">affinity</a> for estrogen receptor beta than for estrogen receptor alpha.[<a class="bk_pop" href="#CDR0000719335_rl_163_6">6</a>]</p><p id="CDR0000719335__109">Some studies suggest that soy may have health benefits, including decreasing risk of <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044005/" class="def">cardiovascular</a> disease and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045333/" class="def">cancer</a>. A link between isoflavones and cancer was discovered in 1987 when it was shown that genistein inhibited a protein tyrosine kinase that is often <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045812/" class="def">overexpressed</a> in cancer cells.[<a class="bk_pop" href="#CDR0000719335_rl_163_7">7</a>] Subsequently, genistein was found to inhibit multiple protein tyrosine kinases relevant to cancer cell proliferation.[<a class="bk_pop" href="#CDR0000719335_rl_163_8">8</a>] In addition, numerous studies have shown that prostate cancer incidence is very low in Asian countries, where diets tend to be high in soy.[<a class="bk_pop" href="#CDR0000719335_rl_163_9">9</a>]</p></div><div id="CDR0000719335__110"><h3>Preclinical/Animal Studies</h3><div id="CDR0000719335__173"><h4><i>In vitro</i> studies</h4><div id="CDR0000719335__112"><h5>Individual isoflavones</h5><p id="CDR0000719335__113">A number of <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044512/" class="def">laboratory studies</a> have examined ways in which soy components affect prostate cancer cells. In one study, human prostate cancer cells and normal prostate <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045682/" class="def">epithelial</a> cells were treated with either an ethanol vehicle (carrier) or isoflavones. Treatment with genistein decreased COX-2 <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000662001/" class="def">mRNA</a> and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046092/" class="def">protein</a> levels in cancer cells and normal epithelial cells more than did treatment with the vehicle. In addition, cells treated with genistein exhibited reduced <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000643082/" class="def">secretion</a> of prostaglandin E2 (PGE2) and reduced mRNA levels of the prostaglandin <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044958/" class="def">receptors</a> EP4 and FP, suggesting that genistein may exert <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045487/" class="def">chemopreventive</a> effects by inhibiting the synthesis of prostaglandins, which promote <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044042/" class="def">inflammation</a>.[<a class="bk_pop" href="#CDR0000719335_rl_163_10">10</a>] In another study, human prostate cancer cells were treated with genistein or daidzein. The isoflavones were shown to down regulate <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045705/" class="def">growth factors</a> involved in <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046529/" class="def">angiogenesis</a> (e.g., <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000653115/" class="def">EGF</a> and IGF-1) and the <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046069/" class="def">interleukin</a>-8 <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000045693/" class="def">gene</a>, which is associated with cancer <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044078/" class="def">progression</a>. These findings suggest that genistein and daidzein may have chemopreventive properties.[<a class="bk_pop" href="#CDR0000719335_rl_163_11">11</a>] Both genistein and daidzein have been shown to reduce the proliferation of LNCaP and PC-3 prostate cancer cells <i><a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045733/" class="def">in vitro</a></i>. However, during the 72 hours of <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045734/" class="def">incubation</a>, only genistein provoked effects on the dynamic <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000460203/" class="def">phenotype</a> and decreased invasiveness in PC-3 cells. These results imply that invasive activity is at least partially dependent on <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046294/" class="def">membrane</a> fluidity and that genistein may exert its antimetastatic effects by changing the mechanical properties of prostate cancer cells. No such effects were observed for daidzein at the same dose.[<a class="bk_pop" href="#CDR0000719335_rl_163_12">12</a>]</p></div><div id="CDR0000719335__114"><h5>Combinations of isoflavones</h5><p id="CDR0000719335__115">Some experiments have compared the effects of individual isoflavones with isoflavone combinations on prostate cancer cells. In one study, human prostate cancer cells were treated with a soy <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000407760/" class="def">extract</a> (containing genistin, daidzin, and glycitin), genistein, or daidzein. The soy extract induced <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000597111/" class="def">cell cycle</a> arrest and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046524/" class="def">apoptosis</a> in prostate cancer cells to a greater degree than did treatment with the individual isoflavones. Genistein and daidzein activated apoptosis in noncancerous <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046509/" class="def">benign prostatic hyperplasia</a> (BPH) cells, but the soy extract had no effect on those cells. These findings suggested that products containing a combination of active <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000422394/" class="def">compounds</a> (e.g., "whole foods") may be more effective in preventing cancer than individual compounds.[<a class="bk_pop" href="#CDR0000719335_rl_163_13">13</a>] Similarly, in another study, prostate cancer cells were treated with genistein, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044148/" class="def">biochanin A</a>, quercetin, doublets of those compounds (e.g., genistein + quercetin), or with all three compounds. All of the treatments resulted in decreased cell proliferation, but the greatest reductions occurred using the combination of genistein, biochanin A, and quercetin. The triple combination treatment induced more apoptosis in prostate cancer cells than did individual or doublet compound treatments. These results indicate that combining phytoestrogens may increase the effectiveness of the individual compounds.[<a class="bk_pop" href="#CDR0000719335_rl_163_14">14</a>]</p><p id="CDR0000719335__116">At least one study has examined the combined effect of soy isoflavones and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046049/" class="def">curcumin</a>. Human prostate cancer cells were treated with isoflavones, curcumin, or a combination of the two. Curcumin and isoflavones in combination were more effective in lowering PSA levels and expression of the <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045592/" class="def">androgen</a> receptor than were curcumin or the isoflavones individually.[<a class="bk_pop" href="#CDR0000719335_rl_163_15">15</a>]</p></div></div><div id="CDR0000719335__117"><h4>Animal studies</h4><p id="CDR0000719335__118"><a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000043996/" class="def">Animal models</a> of prostate cancer have been used in studies investigating the effects of soy and isoflavones on the disease. Wild-type and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000691466/" class="def">transgenic</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046216/" class="def">adenocarcinoma</a> of the mouse prostate (TRAMP) mice were fed control diets or diets containing genistein (250 mg genistein/kg chow). The TRAMP mice fed with genistein exhibited reduced cell proliferation in the prostate compared with TRAMP mice fed a control diet. The genistein-supplemented diet also reduced levels of ERK-1 and ERK-2 (proteins important in stimulating cell proliferation) as well as the growth factor receptors EGFR and IGF-1R in TRAMP mice, suggesting that down regulation of these proteins may be one mechanism by which genistein exerts chemopreventive effects.[<a class="bk_pop" href="#CDR0000719335_rl_163_16">16</a>] In one study, following the appearance of spontaneous <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044345/" class="def">prostatic intraepithelial neoplasia</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046324/" class="def">lesions</a>, TRAMP mice were fed control diets or diets supplemented with genistein (250 or 1,000 mg genistein/kg chow). Mice fed low-dose genistein exhibited more cancer cell metastasis and greater osteopontin expression than mice fed the control or the high-dose genistein diet. These results indicate that timing and dose of genistein treatment may affect prostate cancer outcomes and that genistein may exert biphasic control over prostate cancer.[<a class="bk_pop" href="#CDR0000719335_rl_163_17">17</a>] In a study reported in 2008, athymic mice were implanted with human prostate cancer cells and fed a control or genistein-supplemented diet (100 or 250 mg genistein/kg chow). Mice that were fed genistein exhibited less cancer cell metastasis, but no change in primary tumor volume, than did mice fed a control diet. Furthermore, other data suggested that genistein inhibits metastasis by impairing cancer cell detachment.[<a class="bk_pop" href="#CDR0000719335_rl_163_18">18</a>] In contrast, in a study reported in 2011, there were more metastases in secondary <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000257523/" class="def">organs</a> in genistein-treated mice than in vehicle-treated mice. In this latter study, mice were implanted with human prostate cancer <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044095/" class="def">xenografts</a> and treated daily with genistein dissolved in peanut oil (80 mg genistein/kg body weight/day or 400 mg genistein/kg body weight/day) or peanut oil vehicle by gavage. In addition, there was a reduction in tumor cell apoptosis in the genistein-treated mice compared with the vehicle-treated mice. These findings suggest that genistein may stimulate metastasis in an animal model of <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000478743/" class="def">advanced</a> prostate cancer.[<a class="bk_pop" href="#CDR0000719335_rl_163_19">19</a>]</p><p id="CDR0000719335__119"><a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044971/" class="def">Radiation therapy</a> is commonly used in prostate cancer, but, despite this treatment, disease <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045861/" class="def">recurrence</a> is common. Therefore, combining radiation with additional therapies may provide longer-lasting results. In one study, human prostate cancer cells were treated with soy isoflavones and/or radiation. Cells that were treated with both isoflavones and radiation exhibited greater decreases in cell survival and greater expression of proapoptotic <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045065/" class="def">molecules</a> than cells treated with isoflavones or radiation only. Nude mice were implanted with prostate cancer cells and treated by gavage with genistein (21.5 mg/kg body weight/day), mixed isoflavones (50 mg/kg body weight/day; contained 43% genistein, 21% daidzein, and 2% glycitein) and/or radiation. Mixed isoflavones were more effective than genistein in inhibiting prostate tumor growth, and combining isoflavones with radiation resulted in the largest inhibition of tumor growth. In addition, mice given soy isoflavones in combination with radiation did not exhibit <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045762/" class="def">lymph node</a> metastasis, which was seen previously in other experiments combining genistein with radiation. These preclinical findings suggest that mixed isoflavones may increase the efficacy of radiation therapy for prostate cancer.[<a class="bk_pop" href="#CDR0000719335_rl_163_20">20</a>]</p></div></div><div id="CDR0000719335__120"><h3>Human Studies</h3><p id="CDR0000719335__121">Numerous clinical studies have been conducted examining the impact of soy use on indicators of the effectiveness of prostate cancer prevention or treatment approaches. These studies have included a wide range of participants (from <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000561403/" class="def">healthy control</a> subjects to prostate cancer patients at various stages of the disease) and have used a number of different <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000454757/" class="def">interventions</a> such as soy supplements, beverages, and breads.</p><div id="CDR0000719335__122"><h4>Epidemiologic studies</h4><p id="CDR0000719335__123">In 2009, a <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000691484/" class="def">meta-analysis</a> of studies that investigated soy food consumption and risk of prostate cancer was reported. The results of this meta-analysis suggested that high consumption of nonfermented soy foods (e.g., tofu and soybean milk) may significantly decrease the risk of prostate cancer. No association was found between high consumption of fermented soy foods (e.g., miso) and prostate cancer risk.[<a class="bk_pop" href="#CDR0000719335_rl_163_21">21</a>] An updated 2013 meta-analysis confirmed the good safety profile of isoflavones but indicated no significant differences between treated and control groups for PSA levels or sex <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000613764/" class="def">steroid</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000346519/" class="def">endpoints</a> (sex hormone-binding globulin, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045581/" class="def">testosterone</a>, free testosterone, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000305990/" class="def">estradiol</a> and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000597120/" class="def">dihydrotestosterone</a>).[<a class="bk_pop" href="#CDR0000719335_rl_163_22">22</a>] One study assessed <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044093/" class="def">urinary</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000683342/" class="def">concentrations</a> of phytoestrogens in healthy Jamaican men and men newly <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046450/" class="def">diagnosed</a> with prostate cancer. There were no differences in urinary concentrations of the isoflavones genistein and daidzein between healthy men and prostate cancer patients. Men who produced equol (a <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000462687/" class="def">metabolite</a> of daidzein) were at a lower risk of prostate cancer than men who were nonproducers.[<a class="bk_pop" href="#CDR0000719335_rl_163_23">23</a>]</p></div><div id="CDR0000719335__124"><h4>Prevention studies</h4><p id="CDR0000719335__125">In one study, Japanese men who had undergone prostate <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045164/" class="def">biopsy</a>, but who did not have cancer, were randomly assigned to receive a supplement containing soy isoflavones (40 mg; comprising 66% daidzein, 24% glycitin, and 10% genistin) and curcumin (100 mg) or a <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046688/" class="def">placebo</a> for 6 months. Overall, there were no differences in PSA levels between the placebo and the treatment groups. However, when subjects were subdivided according to <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000467830/" class="def">baseline</a> PSA level, patients with a higher baseline PSA level (PSA ≥10 ng/mL) who received supplements exhibited statistically significantly larger decreases in PSA than did patients in the placebo group (<i>P</i> = .02).[<a class="bk_pop" href="#CDR0000719335_rl_163_15">15</a>]</p><p id="CDR0000719335__126">Although soy is a standard part of many Asian diets, it is less common in Western diets. Therefore, feasibility studies were undertaken to investigate whether Western participants would adhere to soy-supplementation interventions. In one study, healthy men were randomly assigned to consume a low-soy (usual diet) or high-soy (two daily soy servings) diet for 3 months. Following a 1-month washout period, the men crossed over to the other treatment. Reductions approaching statistical significance were seen in PSA levels following the high-soy diet. These findings suggest that this type of soy intervention study is feasible (i.e., the participants complied with dietary instructions) and that soy may be a potential chemopreventive agent.[<a class="bk_pop" href="#CDR0000719335_rl_163_24">24</a>]</p><p id="CDR0000719335__127">In one study, men at risk of prostate cancer or with <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000386213/" class="def">low-grade</a> prostate cancer received one of three types of protein isolate (soy protein, alcohol-washed soy protein [a common method of producing soy protein concentrate that results in some loss of isoflavones], or milk protein) for 6 months. The isoflavone content of the interventions was 107±5.0 mg/day for soy protein isolate (containing 53% genistein, 35% daidzein, and 11% glycitein), <6±0.7 mg/day for alcohol-washed soy protein (containing 57% genistein, 20% daidzein, and 23% glycitein), and 0 mg/day for milk protein. Soy protein consumption did not alter prostate tissue <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045618/" class="def">biomarkers</a>, alcohol-washed soy protein exerted mixed effects, and less prostate cancer was detected after 6 months in men who had consumed soy proteins compared with men who consumed milk protein.[<a class="bk_pop" href="#CDR0000719335_rl_163_25">25</a>]</p><p id="CDR0000719335__549">Japanese men who had <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044088/" class="def">serum</a> PSA levels between 2.5 ng/mL and 10 ng/mL and a previous negative biopsy within 12 months were randomly assigned to receive either <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044068/" class="def">oral</a> isoflavone (60 mg per day) or placebo for 12 months.[<a class="bk_pop" href="#CDR0000719335_rl_163_26">26</a>] One hundred fifty-eight men were enrolled with a <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044941/" class="def">median</a> age of 66 years. There were no differences in PSA values or in incidence of biopsy-detectable prostate cancer before and after treatment in the isoflavone or placebo groups. In a <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000285981/" class="def">subset analysis</a> of the 53 men older than 65 years, 7 of 25 men in the isoflavone group developed prostate cancer, compared with 16 of 28 men in the placebo group (<i>P</i> = .031).</p><p id="CDR0000719335__128">Other plants also contain some of the same isoflavones found in soy. In one study, patients with elevated PSA levels but <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044692/" class="def">negative</a> prostate <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045619/" class="def">biopsy specimens</a> received a daily isoflavone preparation extracted from <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000330178/" class="def">red clover</a> (60 mg/day; which contained the isoflavones genistein, daidzein, formononetin, and biochanin A) and were followed up for 1 year. After 12 months of treatment, there was a significant reduction in PSA levels (<i>P</i> = .019) and a nonsignificant decrease in prostate volume (<i>P</i> = .097). In addition, the isoflavone intervention was well tolerated by the patients and did not cause side effects.[<a class="bk_pop" href="#CDR0000719335_rl_163_27">27</a>]</p></div><div id="CDR0000719335__129"><h4>Treatment of prostate cancer</h4><div id="CDR0000719335__130"><h5>Isoflavones</h5><p id="CDR0000719335__131">In a study reported in 2010, patients with rising PSA levels who had been treated with radiation as the primary treatment for prostate cancer drank a soy beverage daily (providing approximately 65-90 mg isoflavones) for 6 months. The results showed that the soy beverage was well-tolerated and was associated with an increase in PSA doubling time. These findings suggested that drinking the soy beverage may have helped to slow the progression of prostate cancer.[<a class="bk_pop" href="#CDR0000719335_rl_163_28">28</a>]</p><p id="CDR0000719335__150"> In one small (n = 20), <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000285990/" class="def">open-label study</a>, patients with rising PSA levels following previous therapy consumed soy milk three times a day (141 mg isoflavonoid/day) for 12 months. The results showed that drinking soy milk was associated with a greater than 50% decline in PSA level in one patient and decreases in the rate of rise in serum PSA in 14 patients.[<a class="bk_pop" href="#CDR0000719335_rl_163_29">29</a>]</p><p id="CDR0000719335__151">In another study, prostate cancer patients received genistein-rich supplements (450 mg genistein/day, plus 450 mg other aglycone isoflavones/day) for 6 months. The majority of patients who were undergoing <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000616060/" class="def">active surveillance</a> exhibited either no rise in PSA level or a decline of less than 50%.[<a class="bk_pop" href="#CDR0000719335_rl_163_30">30</a>] In a similar study, prostate cancer patients undergoing <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000616060/" class="def">active surveillance</a> were randomly assigned to receive a placebo or an isoflavone supplement containing high doses of genistein and daidzein (450 mg genistein, 300 mg daidzein, and other isoflavones) for 6 months. Then, for an additional 6 months, all participants received the isoflavone supplement. Although treatment with the supplements raised serum concentration levels of genistein and daidzein, there was no effect on PSA levels.[<a class="bk_pop" href="#CDR0000719335_rl_163_31">31</a>]</p><p id="CDR0000719335__152">In a study reported in 2011, prostate cancer patients scheduled for <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046549/" class="def">radical prostatectomy</a> were randomly assigned to receive a placebo or 30 mg genistein daily for 3 to 6 weeks before surgery. Among the patients who received genistein, serum PSA levels decreased by 7.8%, whereas serum PSA levels increased by 4.4% in patients who received the placebo; this difference approached statistical significance (<i>P</i> = .051). In addition, the genistein intervention resulted in significantly lower levels of total <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000407756/" class="def">cholesterol</a> compared with placebo treatment (<i>P</i> = .013).[<a class="bk_pop" href="#CDR0000719335_rl_163_32">32</a>] Another group, however, conducted a <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045858/" class="def">randomized</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044840/" class="def">placebo-controlled</a> trial to examine the effect of soy isoflavone capsules (80 mg/day of total isoflavones) on <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045754/" class="def">localized</a> prostate cancer in 86 men who took the capsules for up to 6 weeks before prostatectomy.[<a class="bk_pop" href="#CDR0000719335_rl_163_33">33</a>] Changes in serum-free and total testosterone, PSA, and total cholesterol were not different between the two groups. The investigators noted that the 12 genes involved in cell cycle control and the 9 genes involved in apoptosis were down regulated in the tumor tissues of the isoflavone-treated men, compared with the controls.</p><p id="CDR0000719335__265">In a phase II, randomized, double-blind, placebo-controlled trial [<a class="bk_pop" href="#CDR0000719335_rl_163_34">34</a>,<a class="bk_pop" href="#CDR0000719335_rl_163_35">35</a>] of men with localized prostate cancer (Gleason score 2–6) who were administered isoflavones (80 mg/day) or a placebo, significant increases in plasma isoflavones (<i>P</i> ≤ .001) were observed from baseline to 4 and 12 weeks in the isoflavone-treated group compared with placebo. Although greater mean reduction of serum-free testosterone was observed in men in the isoflavone-treated group than in men in the placebo group, these changes were not statistically significant for this duration of intervention (<i>P</i> = 0.3). Increasing concentrations of plasma isoflavones daidzein (<i>P</i> = .02) and genistein (<i>P</i> = .01) in the isoflavone-treated group were inversely correlated with changes in serum PSA, compared with the placebo arm. </p><p id="CDR0000719335__281">In a second phase II, multidose, randomized placebo-controlled trial,[<a class="bk_pop" href="#CDR0000719335_rl_163_34">34</a>,<a class="bk_pop" href="#CDR0000719335_rl_163_36">36</a>] 45 men with localized prostate cancer received supplements with either 40, 60, or 80 mg of purified isoflavones or no supplement from the time of biopsy to prostatectomy. Significant increases in plasma isoflavones were observed with all isoflavone doses, compared with placebo, and significant increases in serum total estradiol were observed in the 40 mg and 60 mg isoflavone-treated arms. However, significant increases in serum-free testosterone were observed in the 60 mg isoflavone-treated arm. Compared with the control group and other treatment arms, the 40 mg isoflavone-treated arm had the lowest percentage of cells expressing Ki-67, although this was not statistically significant for this sample size and duration of intervention. This study concluded that 40 mg of isoflavones may be the best dose to use in a future definitive, larger phase II clinical trial to evaluate purified isoflavones in prostate carcinogenesis.</p></div><div id="CDR0000719335__132"><h5>Soy protein</h5><p id="CDR0000719335__133">In one study, early-stage prostate cancer patients were randomly assigned to receive a soy protein supplement (60 mg/day isoflavones) or a placebo daily for 12 weeks. Patients who received the soy protein supplement exhibited larger decreases in total serum PSA and free testosterone than did patients who received the placebo, but these differences were not statistically significant.[<a class="bk_pop" href="#CDR0000719335_rl_163_37">37</a>]</p></div><div id="CDR0000719335__134"><h5>Whole soy products</h5><p id="CDR0000719335__135">Clinical studies have been conducted in prostate cancer patients to test soy as a possible treatment for prostate cancer. In one study, prostate cancer patients scheduled to undergo <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046549/" class="def">radical prostatectomy</a> were randomly assigned to receive soy supplements (three 27.2 mg tablets/day; each tablet contained 10.6 mg genistein, 13.3 mg daidzein, and 3.2 mg glycitein) or a placebo for 2 weeks before surgery. The isoflavone concentration in prostatic tissue was sixfold higher than in serum following treatment with the soy supplements, suggesting that the prostate may accumulate potentially <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044272/" class="def">anticarcinogenic</a> levels of isoflavones.[<a class="bk_pop" href="#CDR0000719335_rl_163_38">38</a>] In another study, prostate cancer patients scheduled for radical prostatectomy were instructed to eat bread containing high levels of phytoestrogens (soy or soy + <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000285921/" class="def">linseed</a>; 117 mg/day isoflavones) or low levels of phytoestrogens (wheat bread) until surgery. Patients who ate the high-phytoestrogen bread saw more favorable changes in PSA levels than did patients who ate the wheat bread, indicating that diets rich in phytoestrogens may help to reduce risk of prostate cancer development and progression.[<a class="bk_pop" href="#CDR0000719335_rl_163_39">39</a>]</p><p id="CDR0000719335__136">In a small study, ten men with prostate cancer recurrence were advised to consume three 8-ounce glasses of soy milk every day for 2 years. Clinical benefits (i.e., decreased, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044580/" class="def">attenuated</a>, or stabilized PSA) were observed in five of the ten participants, suggesting that soy products may have positive effects in some prostate cancer patients.[<a class="bk_pop" href="#CDR0000719335_rl_163_40">40</a>]</p></div></div><div id="CDR0000719335__137"><h4>Management of hormone therapy side-effects</h4><p id="CDR0000719335__138"><a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000559086/" class="def">Androgen deprivation</a> therapy is commonly used for <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045955/" class="def">locally advanced</a> and metastatic prostate cancer. However, this treatment is associated with a number of adverse side effects including sexual dysfunction, decreased <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045417/" class="def">quality of life</a>, and changes in <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000476290/" class="def">cognition</a>. Two studies have examined men undergoing androgen deprivation therapy who were randomly assigned to receive a placebo or an isoflavone supplement (soy protein powder mixed with beverages; 160 mg/day isoflavones) for 12 weeks. Neither study found an improvement in side effects following isoflavone treatment, compared with placebo treatment.[<a class="bk_pop" href="#CDR0000719335_rl_163_41">41</a>,<a class="bk_pop" href="#CDR0000719335_rl_163_42">42</a>]</p></div><div id="CDR0000719335__139"><h4>Effects on inflammatory parameters</h4><p id="CDR0000719335__140">In a study of men undergoing androgen deprivation therapy, participants were randomly assigned to receive high-dose isoflavone supplements (providing 160 mg/day total isoflavones and containing 64 mg genistein, 63 mg daidzein, and 34 mg glycitein) or a placebo for 12 weeks. The results showed no difference between the two groups in PSA levels or in levels of <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044056/" class="def">metabolic</a> and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000373080/" class="def">inflammatory</a> parameters (e.g., <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044033/" class="def">glucose</a>, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044045/" class="def">interleukin-6</a>).[<a class="bk_pop" href="#CDR0000719335_rl_163_43">43</a>]</p><p id="CDR0000719335__141">Prostaglandins promote <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044042/" class="def">inflammation</a> and may contribute to cancer by increasing cell proliferation and inhibiting apoptosis. The findings of a study reported in 2009 suggest that soy isoflavones may have chemopreventive effects via inhibition of the prostaglandin pathway. In the study, prostate cancer patients scheduled to undergo prostatectomy were randomly assigned to receive a placebo or a soy isoflavone supplement (providing 81.6 mg/day isoflavones) for at least 2 weeks before surgery. The results showed a significant decrease in COX-2 mRNA levels (<i>P</i> < .01) and significant increases in p21 mRNA levels (<i>P</i> < .01) in prostatectomy specimens obtained from the soy-supplemented group compared with specimens from the placebo group.[<a class="bk_pop" href="#CDR0000719335_rl_163_10">10</a>]</p></div><div id="CDR0000719335__170"><h4>Current clinical trials</h4><p id="CDR0000719335__171">Check NCI’s list of cancer clinical trials for CAM clinical trials on <a href="https://www.cancer.gov/about-cancer/treatment/clinical-trials/search/results?protocolsearchid=10188078&vers=1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">soy isoflavones for prostate cancer</a> and <a href="https://www.cancer.gov/about-cancer/treatment/clinical-trials/search/results?protocolsearchid=10465113&vers=1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">soy protein isolate for prostate cancer</a> that are actively enrolling patients.</p><p id="CDR0000719335__172">General information about clinical trials is also available from the <a href="https://www.cancer.gov/about-cancer/treatment/clinical-trials" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NCI website</a>.</p></div></div><div id="CDR0000719335__142"><h3>Adverse Effects</h3><p id="CDR0000719335__143">Overall, soy was well tolerated in clinical studies of prostate cancer patients.[<a class="bk_pop" href="#CDR0000719335_rl_163_24">24</a>,<a class="bk_pop" href="#CDR0000719335_rl_163_27">27</a>,<a class="bk_pop" href="#CDR0000719335_rl_163_29">29</a>,<a class="bk_pop" href="#CDR0000719335_rl_163_31">31</a>,<a class="bk_pop" href="#CDR0000719335_rl_163_38">38</a>,<a class="bk_pop" href="#CDR0000719335_rl_163_41">41</a>] The most commonly reported side effects were gastrointestinal symptoms.[<a class="bk_pop" href="#CDR0000719335_rl_163_28">28</a>,<a class="bk_pop" href="#CDR0000719335_rl_163_30">30</a>,<a class="bk_pop" href="#CDR0000719335_rl_163_31">31</a>] In addition, one study reported that a participant withdrew due to <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044043/" class="def">insomnia</a>.[<a class="bk_pop" href="#CDR0000719335_rl_163_28">28</a>]</p></div><div id="CDR0000719335_rl_163"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000719335_rl_163_1">Barnes S: The biochemistry, chemistry and physiology of the isoflavones in soybeans and their food products. 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[<a href="/pmc/articles/PMC3710024/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3710024</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/23874588" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23874588</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_163_34">Kumar NB, Krischer JP, Allen K, et al.: A Phase II randomized, placebo-controlled clinical trial of purified isoflavones in modulating steroid hormones in men diagnosed with localized prostate cancer. Nutr Cancer 59 (2): 163-8, 2007. 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[<a href="/pmc/articles/PMC3277948/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3277948</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/20205984" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20205984</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_163_37">Kumar NB, Cantor A, Allen K, et al.: The specific role of isoflavones in reducing prostate cancer risk. Prostate 59 (2): 141-7, 2004. [<a href="https://pubmed.ncbi.nlm.nih.gov/15042614" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15042614</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_163_38">Gardner CD, Oelrich B, Liu JP, et al.: Prostatic soy isoflavone concentrations exceed serum levels after dietary supplementation. Prostate 69 (7): 719-26, 2009. [<a href="/pmc/articles/PMC2734961/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2734961</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19180569" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19180569</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_163_39">Dalais FS, Meliala A, Wattanapenpaiboon N, et al.: Effects of a diet rich in phytoestrogens on prostate-specific antigen and sex hormones in men diagnosed with prostate cancer. Urology 64 (3): 510-5, 2004. [<a href="https://pubmed.ncbi.nlm.nih.gov/15351581" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15351581</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_163_40">Joshi M, Agostino NM, Gingrich R, et al.: Effects of commercially available soy products on PSA in androgen-deprivation-naïve and castration-resistant prostate cancer. South Med J 104 (11): 736-40, 2011. [<a href="https://pubmed.ncbi.nlm.nih.gov/22024780" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22024780</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_163_41">Sharma P, Wisniewski A, Braga-Basaria M, et al.: Lack of an effect of high dose isoflavones in men with prostate cancer undergoing androgen deprivation therapy. J Urol 182 (5): 2265-72, 2009. [<a href="/pmc/articles/PMC3089061/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3089061</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19758646" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19758646</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_163_42">Vitolins MZ, Griffin L, Tomlinson WV, et al.: Randomized trial to assess the impact of venlafaxine and soy protein on hot flashes and quality of life in men with prostate cancer. J Clin Oncol 31 (32): 4092-8, 2013. [<a href="/pmc/articles/PMC3816959/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3816959</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/24081940" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24081940</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_163_43">Napora JK, Short RG, Muller DC, et al.: High-dose isoflavones do not improve metabolic and inflammatory parameters in androgen-deprived men with prostate cancer. J Androl 32 (1): 40-8, 2011 Jan-Feb. [<a href="/pmc/articles/PMC3005077/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3005077</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/20798386" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20798386</span></a>]</div></li></ol></div></div><div id="CDR0000719335__357"><h2 id="_CDR0000719335__357_">Vitamin D</h2><div id="CDR0000719335__358"><h3>Overview</h3><ul id="CDR0000719335__359"><li class="half_rhythm"><div><a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000427253/" class="def">Vitamin D</a> is made naturally by the body when exposed to sunlight.</div></li><li class="half_rhythm"><div><a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044517/" class="def">Preclinical studies</a> suggest that vitamin D may have effects on <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000445079/" class="def">prostate cancer</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046476/" class="def">cells</a> through various pathways.</div></li><li class="half_rhythm"><div>Numerous <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000257225/" class="def">epidemiological</a> studies have researched the relationship between vitamin D and prostate cancer.</div></li><li class="half_rhythm"><div>Some <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000454757/" class="def">intervention</a> studies have focused on <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045408/" class="def">calcitriol</a>, the hormonally active form of vitamin D, in prostate cancer patients.</div></li></ul></div><div id="CDR0000719335__361"><h3>General Information and History</h3><p id="CDR0000719335__362">Vitamin D, also called calciferol, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000427252/" class="def">cholecalciferol</a> (D3), or <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000655060/" class="def">ergocalciferol</a> (D2), is a <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000560348/" class="def">fat-soluble vitamin</a> found in fatty fish, fish liver oil, eggs, and fortified dairy products. Vitamin D is made naturally by the body when exposed to sunlight.</p><p id="CDR0000719335__398">In 1922, researchers discovered that heated, oxidized cod-liver oil, called "fat-soluble factor A" and later known as vitamin D, played an important role in <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000318813/" class="def">curing</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000655123/" class="def">rickets</a> in rats.[<a class="bk_pop" href="#CDR0000719335_rl_357_1">1</a>]</p><p id="CDR0000719335__399">Vitamin D performs many roles in the body, including the following:</p><ul id="CDR0000719335__400"><li class="half_rhythm"><div>Promotes <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000463702/" class="def">absorption</a> of <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045632/" class="def">calcium</a> in the <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046582/" class="def">small intestine</a>.</div></li><li class="half_rhythm"><div>Improves muscle strength and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045721/" class="def">immune function</a>.</div></li><li class="half_rhythm"><div>Helps to reduce <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044042/" class="def">inflammation</a>.</div></li><li class="half_rhythm"><div>Helps to maintain adequate <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000270735/" class="def">blood</a> levels of calcium and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000476349/" class="def">phosphate</a>.</div></li></ul><p id="CDR0000719335__401">Vitamin D is needed for bone growth and protects against <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045371/" class="def">osteoporosis</a> in adults.[<a class="bk_pop" href="#CDR0000719335_rl_357_2">2</a>] Vitamin D status is usually checked by measuring the level of 25-hydroxyvitamin D in the blood.</p></div><div id="CDR0000719335__363"><h3>Preclinical/Animal Studies</h3><div id="CDR0000719335__364"><h4><i>In vitro</i> studies</h4><p id="CDR0000719335__365">To study the role of vitamin D in cancer cell adhesion to endothelium, one study developed a microtube system that simulates the microvasculature of <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045622/" class="def">bone marrow</a>. The study reported that 1,25-alpha-dihydroxyvitamin D3 (1,25-D3) suppressed adhesion of prostate cancer cells in the microtube system. In addition, it was shown that 1,25-D3 increased E-cadherin expression, which may prevent prostate cancer cell adhesion to endothelium by promoting cancer cell aggregation.[<a class="bk_pop" href="#CDR0000719335_rl_357_3">3</a>]</p><p id="CDR0000719335__402">Vitamin D–binding <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046092/" class="def">protein</a> (VDBP) transports vitamin D in the bloodstream. Studies have shown that one of its products, VDBP-<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044054/" class="def">macrophage</a> activating factor (VDBP-maf), may have <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044186/" class="def">antiangiogenic</a> and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000446109/" class="def">antitumor</a> activities. One study examined the effects of VDBP-maf on prostate cancer cells. Treating prostate cancer cells with VDBP-maf resulted in inhibited cellular migration, proliferation, and reduced levels of <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000658871/" class="def">urokinase plasminogen activator</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044958/" class="def">receptor</a> (uPAR; activity of this receptor correlates with <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046634/" class="def">tumor</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046710/" class="def">metastasis</a>). These findings suggest that VDBP-maf has a direct effect on prostate cancer cells.[<a class="bk_pop" href="#CDR0000719335_rl_357_4">4</a>]</p><p id="CDR0000719335__403">Studies have reported that 1,25-D3 may play an important role in prostate cancer biology. Studies have suggested that a newly discovered protein, protein disulfide isomerase family A, member 3 (PDIA3), may function as a <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046294/" class="def">membrane</a> receptor binding to 1,25-D3. According to one study, PDIA3 is expressed in normal prostate cells as well as in LNCaP and PC-3 prostate cancer <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000695994/" class="def">cell lines</a>. In addition, their findings suggest that 1,25-D3 may act on prostate cancer cells via multiple signaling pathways, indicating there may be a number of potential <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000043985/" class="def">therapeutic</a> targets.[<a class="bk_pop" href="#CDR0000719335_rl_357_5">5</a>]</p></div><div id="CDR0000719335__368"><h4><i>In vivo</i> studies</h4><p id="CDR0000719335__404"><a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045669/" class="def">Tumor progression</a> was compared in two murine models of prostate cancer. In vitamin D receptor- knockout animals, rate of tumor progression and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046479/" class="def">cellular proliferation</a> were greater than in wild type animals. However, in mice that were supplemented with <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045581/" class="def">testosterone</a>, these differences did not occur, suggesting that there may be <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000390271/" class="def">significant</a> interaction between <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045592/" class="def">androgen</a> signaling and vitamin D signaling.[<a class="bk_pop" href="#CDR0000719335_rl_357_6">6</a>]</p><p id="CDR0000719335__369">In a 2011 study, nude mice were fed a control <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044660/" class="def">diet</a> or a diet deficient in vitamin D and were then <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044678/" class="def">injected</a> with prostate cancer cells into bone marrow or into <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045882/" class="def">soft tissues</a>. <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045810/" class="def">Osteolytic</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046324/" class="def">lesions</a> were larger and progressed at a faster rate in vitamin D–deficient mice that had bone marrow injected with cancer cells than in mice that had adequate levels of vitamin D. However, there was no difference in soft tissue tumors among mice with different vitamin D levels. Results of this study show that vitamin D <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000321364/" class="def">deficiency</a> is associated with growth of prostate cancer cells in bone but not in soft tissue.[<a class="bk_pop" href="#CDR0000719335_rl_357_7">7</a>]</p><p id="CDR0000719335__483">A 2014 study evaluated calcitriol and a less-calcemic vitamin D <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044919/" class="def">analog</a> in an aggressive <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000691466/" class="def">transgenic</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046216/" class="def">adenocarcinoma</a> of the mouse prostate (TRAMP) model. Neither vitamin D analog impacted the rate of development of <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045636/" class="def">castration</a>-resistant prostate cancer in mice, whether they were treated before or after castration. However, both vitamin D analogs slowed progression of primary tumors in hormone-intact mice but enhanced distant <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000257523/" class="def">organ</a> metastases after prolonged treatment. In sum, intervention with potent vitamin D compounds in TRAMP mice slowed androgen-stimulated tumor progression but, over time, may have led to more aggressive disease as indicated by increased <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000415317/" class="def">distant metastases</a> (<i>P</i> = .0823).[<a class="bk_pop" href="#CDR0000719335_rl_357_8">8</a>] This preclinical data supports findings of the 2008 <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044956/" class="def">retrospective study</a> [<a class="bk_pop" href="#CDR0000719335_rl_357_9">9</a>] of an association between <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044088/" class="def">serum</a> vitamin D levels and aggressive prostate cancer (refer to the <a href="#CDR0000719335__375">Human Studies</a> section in the <a href="#CDR0000719335__357">Vitamin D</a> section of this summary for more information about this study).</p></div><div id="CDR0000719335__372"><h4>Vitamin D as adjuvant therapy</h4><p id="CDR0000719335__373"><a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045985/" class="def">Cryotherapy</a> may be used for treating prostate cancer. Studies have been conducted to identify potential agents that may help improve <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000346517/" class="def">efficacy</a> of the freezing procedure. In a 2010 study, mice were injected with prostate cancer cells and treated with calcitriol, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000518326/" class="def">cryoablation</a>, or both. The combination treatment group experienced larger necrotic areas, more <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046524/" class="def">apoptosis</a>, and less cell proliferation than did the other <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044758/" class="def">experimental</a> groups.[<a class="bk_pop" href="#CDR0000719335_rl_357_10">10</a>] A subsequent study corroborated these findings, showing that combining calcitriol and cryoablation resulted in more cell death than cryotherapy alone.[<a class="bk_pop" href="#CDR0000719335_rl_357_11">11</a>]</p><p id="CDR0000719335__374">Vitamin D may help enhance other types of cancer treatments, such as <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045072/" class="def">radiation</a>. In another study, prostate cancer cells were treated with <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000367423/" class="def">valproic acid</a> (VPA) and/or 1,25-D3, followed by radiation. Cells that were treated with VPA and/or 1,25-D3 and radiation had greater decreases in cell proliferation than did cells treated solely with radiation. The greatest reduction in cell proliferation occurred in cells treated with VPA, 1,25-D3, and radiation.[<a class="bk_pop" href="#CDR0000719335_rl_357_12">12</a>]</p></div></div><div id="CDR0000719335__375"><h3>Human Studies</h3><div id="CDR0000719335__376"><h4>Epidemiological studies</h4><p id="CDR0000719335__377">The relationship between vitamin D and prostate cancer has been examined in numerous epidemiological studies. Vitamin D levels were analyzed annually for 5 years in patients with <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045805/" class="def">nonmetastatic</a> prostate cancer. Results showed that throughout the course of the study, vitamin D insufficiency was prevalent among these cancer patients.[<a class="bk_pop" href="#CDR0000719335_rl_357_13">13</a>] Levels of vitamin D metabolites in prostate cancer patients were examined in a 2011 study. <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000390238/" class="def">Analysis</a> revealed that patients with the lowest concentrations of prediagnostic <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045839/" class="def">plasma</a> 25-hydroxy vitamin D [25(OH)D] levels had a higher risk of developing <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044058/" class="def">metastatic</a> prostate cancer than did patients with higher levels of 25(OH)D. However, there was no association between metastatic prostate cancer and circulating levels of 1,25(OH)D.[<a class="bk_pop" href="#CDR0000719335_rl_357_14">14</a>] In another study, serum levels of 25(OH)D in prostate cancer patients were assessed. Results suggest that medium or high levels of serum 25(OH)D may be associated with better prognoses than lower levels of serum 25(OH)D. These findings indicate that 25(OH)D may play a role in <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045669/" class="def">disease progression</a> and may be a marker of <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045849/" class="def">prognosis</a> in prostate cancer patients.[<a class="bk_pop" href="#CDR0000719335_rl_357_15">15</a>] Participants in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) study who had been <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046450/" class="def">diagnosed</a> with prostate cancer and control participants were selected for analysis and monitored for up to 20 years. Results suggested that men with a higher vitamin D status (assessed via serum 25(OH)D concentrations) had a greater risk of developing prostate cancer than did men with lower vitamin D status.[<a class="bk_pop" href="#CDR0000719335_rl_357_16">16</a>] A 2008 retrospective study of 749 men with prostate cancer diagnosed 1 to 8 years after blood draw and 781 matched controls found higher circulating 25(OH)D concentrations may be associated with increased risk of aggressive disease.[<a class="bk_pop" href="#CDR0000719335_rl_357_9">9</a>] Both of these studies [<a class="bk_pop" href="#CDR0000719335_rl_357_9">9</a>,<a class="bk_pop" href="#CDR0000719335_rl_357_16">16</a>] were included in a <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000691484/" class="def">meta-analysis</a> of 21 studies, involving 11,941 cases and 13,870 controls, that found a 17% elevated risk of prostate cancer in men with higher levels of 25(OH)D.[<a class="bk_pop" href="#CDR0000719335_rl_357_17">17</a>] One explanation offered for this finding may be a potential detection bias with men from higher socio-economic groups who have higher vitamin D levels and who are more likely to undergo <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046540/" class="def">prostate-specific antigen</a> (PSA) <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000322878/" class="def">testing</a>, resulting in higher reported incidence rates.</p><p id="CDR0000719335__510">In one <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000348989/" class="def">case-control study</a> of men who had undergone prostate <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045164/" class="def">biopsies</a>, men who had lower vitamin D levels before biopsy were more likely to have cancer detected at biopsy than did men whose prebiopsy vitamin D levels were not lower.[<a class="bk_pop" href="#CDR0000719335_rl_357_18">18</a>] Serum 25(OH)D levels were obtained from 667 men in Chicago undergoing first prostate biopsy for an elevated PSA or an abnormal digital rectal exam.[<a class="bk_pop" href="#CDR0000719335_rl_357_18">18</a>] Severe vitamin D deficiency (<12 <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000285977/" class="def">ng</a>/<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044214/" class="def">mL</a>) was associated with increased risk of a prostate cancer diagnosis on biopsy among African American men. Severe deficiency was positively associated with higher <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045696/" class="def">Gleason score</a> (≥4+4), higher clinical stage (>cT2b), and overall risk category in both white American and African American men. In contrast, baseline serum 25(OH)D levels obtained in a case (n = 1,731)–cohort (n = 3,203) analysis from the Selenium and Vitamin E Cancer Prevention Trial found significantly reduced risks among men who had moderate concentrations (45–70 nmol/L) compared with men who had lower or higher values.[<a class="bk_pop" href="#CDR0000719335_rl_357_19">19</a>] This U-shaped association was most pronounced for cancers with Gleason scores of 7 to 10. One hundred ninety men who participated in a large epidemiologic study underwent <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046549/" class="def">radical prostatectomy</a> for clinically <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045754/" class="def">localized</a> prostate cancer.[<a class="bk_pop" href="#CDR0000719335_rl_357_20">20</a>] At the time of <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045851/" class="def">prostatectomy</a>, 87 men (45.8%) exhibited adverse pathology, defined as primary Gleason 4, any Gleason 5 or extraprostatic extension. Men with adverse pathology had lower <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044941/" class="def">median</a> serum 25(OH)D (22.7 ng/mL), compared with their counterparts (27.0 ng/mL), and were also more likely to have a serum 25(OH)D level less than 30 ng/mL.</p><p id="CDR0000719335__378">An important means of obtaining vitamin D is via sunlight. Studies have investigated the potential link between sunlight exposure and prostate cancer. According to a 2006 study, PSA levels rise at a slower rate during spring and summer than at other times of the year; this may be related to higher vitamin D levels obtained during those months.[<a class="bk_pop" href="#CDR0000719335_rl_357_21">21</a>] One study found that while men with low levels of sun exposure had increased risk of all prostate cancers, among men with prostate cancer, less sun exposure was associated with lower risk of advanced disease. Results of a meta-analysis, published in the same report, showed that men with low sun exposure had an increased risk of incident and advanced prostate cancer.[<a class="bk_pop" href="#CDR0000719335_rl_357_22">22</a>] Analysis of <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000496502/" class="def">mortality</a> rate data from 1950 to 1994 revealed that the geographic distribution of prostate cancer mortality in the United States is inversely related to <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044472/" class="def">UV radiation</a>. In addition, this relationship is more evident in areas north of 40 degrees N latitude.[<a class="bk_pop" href="#CDR0000719335_rl_357_23">23</a>] Likewise, a study in France reported that UV radiation may be associated with reductions in cancer risk and mortality.[<a class="bk_pop" href="#CDR0000719335_rl_357_24">24</a>]</p><p id="CDR0000719335__379">A number of studies have explored a possible connection between the vitamin D receptor (VDR) and risk of prostate cancer. A 2011 <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044079/" class="def">prospective</a> study examined VDR expression in prostate tumors. Patients with high levels of VDR expression had lower PSA at diagnosis, less <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000478743/" class="def">advanced</a> tumor stage, and reduced risk of lethal prostate cancer compared with patients with lower levels of VDR expression in tumors.[<a class="bk_pop" href="#CDR0000719335_rl_357_25">25</a>] In a 2009 study, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046391/" class="def">genetic</a> variants in VDR were analyzed in prostate cancer patients participating in the Prostate Testing for Cancer and Treatment (ProtecT) trial. Five <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000044805/" class="def">polymorphisms</a> of VDR were identified in the participants. A meta-analysis, published in the same report, revealed no association between specific variants and prostate cancer stage (<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000672851/" class="def">TNM staging system</a>), but found that three genotypes (<i>BSML</i>, <i>APAL</i>, and <i>TAQL</i>) may be associated with cancer grade (Gleason score), suggesting there may be a link between specific VDR polymorphisms and advanced prostate cancer at diagnosis.[<a class="bk_pop" href="#CDR0000719335_rl_357_26">26</a>] Polymorphisms in the VDR receptor, the vitamin D activating <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046081/" class="def">enzyme</a> 1-alpha-hydroxylase (CYP27B1), and deactivating enzyme 24-hydroxylase (CYP24A1) were examined in a 2010 study. Variations in the three <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000045693/" class="def">genes</a> investigated were associated with changes in risk of <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045861/" class="def">recurrence</a> and progression of prostate cancer as well as prostate cancer mortality.[<a class="bk_pop" href="#CDR0000719335_rl_357_27">27</a>] A case-control study analyzed the correlation between VDBP single nucleotide polymorphisms (SNPs) and prostate cancer risk. Two SNPs in VDBP were associated with increased prostate cancer risk and high Gleason grade.[<a class="bk_pop" href="#CDR0000719335_rl_357_28">28</a>] However in another large cohort-consortium study, statistically significant association was not observed for either 25(OH)D or vitamin D-related SNPs with fatal prostate cancer.[<a class="bk_pop" href="#CDR0000719335_rl_357_29">29</a>]</p><p id="CDR0000719335__405">A 2008 meta-analysis of 45 <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000286105/" class="def">observational studies</a> found no association between intake of vitamin D and prostate cancer risk.[<a class="bk_pop" href="#CDR0000719335_rl_357_30">30</a>] A meta-analysis published in 2011 reviewed 25 studies examining the link between prostate cancer <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046145/" class="def">incidence</a> and indicators of vitamin D. Analysis of those studies found no association between dietary vitamin D or circulating concentrations of vitamin D and risk of prostate cancer.[<a class="bk_pop" href="#CDR0000719335_rl_357_31">31</a>]</p></div><div id="CDR0000719335__380"><h4>Intervention studies</h4><p id="CDR0000719335__381">Calcitriol, the hormonally active form of vitamin D, has been the focus of some studies in prostate cancer patients. In an <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000285990/" class="def">open-label</a>, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045831/" class="def">phase II</a> study, patients with recurrent prostate cancer were treated with calcitriol and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000615394/" class="def">naproxen</a> for 1 year. The combination of calcitriol and naproxen was effective in decreasing the rate of rising PSA levels in study participants, suggesting it may slow disease progression.[<a class="bk_pop" href="#CDR0000719335_rl_357_32">32</a>] In a 2010 study, patients with castration-resistant prostate cancer were treated with calcitriol and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045262/" class="def">dexamethasone</a>. The results indicated that while the treatments were well tolerated, they did not have an effect on participants' PSA levels.[<a class="bk_pop" href="#CDR0000719335_rl_357_33">33</a>]</p><p id="CDR0000719335__382">In a 2009 study, patients with <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045955/" class="def">locally advanced</a> or metastatic prostate cancer and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046520/" class="def">asymptomatic</a> progression of their PSA levels were treated with <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000655061/" class="def">vitamin D2</a> (ergocalciferol) at either 10 <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000306521/" class="def">μg</a> or 25 μg daily. The investigators reported that about 20% of these patients had at least a 25% drop in PSA level 3 months after initiating the vitamin D2.[<a class="bk_pop" href="#CDR0000719335_rl_357_34">34</a>]</p></div><div id="CDR0000719335__407"><h4>Current clinical trials</h4><p id="CDR0000719335__408">Check NCI’s list of cancer clinical trials for CAM clinical trials on <a href="https://www.cancer.gov/about-cancer/treatment/clinical-trials/search/results?protocolsearchid=12112431&vers=1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">vitamin D</a> that are actively enrolling patients.</p><p id="CDR0000719335__409">General information about clinical trials is also available from the <a href="https://www.cancer.gov/about-cancer/treatment/clinical-trials" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NCI website</a>.</p></div></div><div id="CDR0000719335__385"><h3>Adverse Effects</h3><div id="CDR0000719335__550"><h4>Vitamin D toxicity</h4><p id="CDR0000719335__551">In most cases, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045022/" class="def">symptoms</a> of vitamin D <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000445093/" class="def">toxicity</a> are caused by <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045363/" class="def">hypercalcemia</a>, but limited evidence suggests high concentrations of vitamin D may also be expressed in various organs, including the <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046325/" class="def">kidneys</a>, bones, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046481/" class="def">central nervous system</a>, and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044005/" class="def">cardiovascular</a> system. Symptoms of toxicity may be observed at an intake of 10,000 to 50,000 <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044764/" class="def">IU</a> per day over a period of many years. Hypercalcemia results from the vitamin D–dependent increase in <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044046/" class="def">intestinal</a> absorption of calcium, leading to rapid increases in blood calcium levels. <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046580/" class="def">Side effects</a> include loss of the <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044093/" class="def">urinary</a> concentrating mechanism of the kidney tubule (resulting in polyuria and polydipsia), decrease in growth factor receptor, hypercalciuria, and the metastatic <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044317/" class="def">calcification</a> of soft tissues. The central <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000446114/" class="def">nervous system</a> may also be affected, resulting in severe <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000430479/" class="def">depression</a> and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044103/" class="def">anorexia</a>.[<a class="bk_pop" href="#CDR0000719335_rl_357_35">35</a>]</p><p id="CDR0000719335__552">A systematic review of the interactions and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044324/" class="def">pharmacokinetics</a> of vitamin D and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000348921/" class="def">drugs</a> used for the treatment of cancer was published.[<a class="bk_pop" href="#CDR0000719335_rl_357_36">36</a>] Based on the review, 26 articles met the inclusion criteria. Calcitriol was the most commonly administered form of vitamin D, and adults with prostate cancer and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045301/" class="def">solid tumors</a> were the most well-represented populations in this systematic review. Hypercalcemia (at a <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044664/" class="def">dose</a> of 74 μg/wk [3,000 IU]; 125 μg/wk [5,000 IU] with the addition of dexamethasone) was the most frequently reported side effect. <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000687890/" class="def">Hypophosphatemia</a> was also observed in two studies [<a class="bk_pop" href="#CDR0000719335_rl_357_37">37</a>,<a class="bk_pop" href="#CDR0000719335_rl_357_38">38</a>] that administered vitamin D in conjunction with <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045382/" class="def">docetaxel</a> in men with prostate cancer. The authors concluded that no <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044922/" class="def">adverse effects</a> were experienced beyond what was expected from high-dose calcitriol <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045916/" class="def">supplementation</a> and was denoted as having a low risk of interaction. Some chemotherapeutic <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045864/" class="def">regimens</a> appear to reduce serum 25(OH)-D3 and/or 1,25-D3. </p><p id="CDR0000719335__553">A number of studies evaluated the safety and efficacy of high-dose calcitriol in conjunction with <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045214/" class="def">chemotherapy</a> drugs in men with androgen-independent prostate cancer, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000686077/" class="def">hormone-refractory</a> prostate cancer, and metastatic castration-resistant prostate cancer.[<a class="bk_pop" href="#CDR0000719335_rl_357_38">38</a>-<a class="bk_pop" href="#CDR0000719335_rl_357_40">40</a>] In the studies utilizing docetaxel plus calcitriol for men with androgen-independent prostate cancer, no increased toxicity was observed when compared with docetaxel alone. </p><p id="CDR0000719335__554">In men with hormone-refractory prostate cancer, one study examined the activity and tolerability of weekly high-dose calcitriol (32 μg/wk [1,300 IU]) with docetaxel in patients who had previously received docetaxel treatment.[<a class="bk_pop" href="#CDR0000719335_rl_357_37">37</a>] Calcitriol was given <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044068/" class="def">orally</a> in three divided doses, and docetaxel was given <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046682/" class="def">intravenously</a> (30 <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044213/" class="def">mg</a>/m<sup>2</sup>) with dexamethasone (8 mg) orally 12 hours before, at the time of, and 12 hours after docetaxel <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000478733/" class="def">administration</a>. Most of the side effects were expected toxicities related to the chemotherapy. Grade 2 hypercalcemia was observed in one patient. Administration of calcitriol was discontinued until hypercalcemia resolved. Supplementation was restarted after two weeks. In another patient, persistent grade 3 <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000321374/" class="def">fatigue</a> was observed, and treatment of calcitriol was discontinued as docetaxel was reduced. </p></div><div id="CDR0000719335__555"><h4>Phase I trials</h4><p id="CDR0000719335__556"><a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045830/" class="def">Phase I</a> studies have looked at the <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000546597/" class="def">maximum tolerated dose</a> (MTD) of weekly intravenous and oral calcitriol in conjunction with various chemotherapy drugs for cancer treatment. One study examined the MTD of calcitriol in conjunction with <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000258356/" class="def">gefitinib</a> at 250 mg/day (<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000689103/" class="def">oral chemotherapy</a> used to treat <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000445043/" class="def">lung cancer</a>) in 32 patients with advanced solid tumors that were metastatic or <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045936/" class="def">unresectable</a>.[<a class="bk_pop" href="#CDR0000719335_rl_357_41">41</a>] At doses up to 74 μg (3,000 IU) per week, no <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044170/" class="def">dose-limiting</a> toxicities were observed. Grade 2 hypercalcemia was observed in two of four patients receiving 96 μg per week (3,900 IU) of calcitriol and was denoted nontolerable. No <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000390271/" class="def">significant</a> bone marrow suppression was observed at any dose. A dose of 74 μg (3,000 IU) per week was denoted as the MTD. The study suggests no major interaction between calcitriol and gefitinib. </p><p id="CDR0000719335__557">A second phase I study examined the MTD and pharmacokinetics of calcitriol when administered with <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045258/" class="def">paclitaxel</a> over the course of 6 weeks.[<a class="bk_pop" href="#CDR0000719335_rl_357_42">42</a>] Thirty-six patients (<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044282/" class="def">heterogenous</a> diagnoses) were enrolled in the trial and received escalating doses of oral calcitriol starting at 4 μg (160 IU) for 3 consecutive days, and increasing to 38 μg (1,520 IU) with an 80-mg/m<sup>2</sup>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045738/" class="def">infusion</a> of paclitaxel given weekly. Results demonstrate that very high doses of calcitriol can be safely administered with paclitaxel. There was no dose-limiting toxicity in the trial, and at a dose of 38 μg/wk, no clinically significant hypercalcemia occurred. However, it is important to note that participants were administered from 8 to 76 <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000455334/" class="def">capsules</a> of calcitriol with no report of adherence to the <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044711/" class="def">prescribed</a> dose of calcitriol. </p></div></div><div id="CDR0000719335_rl_357"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000719335_rl_357_1">Wolf G: The discovery of vitamin D: the contribution of Adolf Windaus. J Nutr 134 (6): 1299-302, 2004. [<a href="https://pubmed.ncbi.nlm.nih.gov/15173387" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15173387</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_357_2">National Institutes of Health. Office of Dietary Supplements: Dietary Supplement Fact Sheet: Vitamin D. Bethesda, MD: National Institutes of Health, 2011. <a href="http://ods.od.nih.gov/factsheets/VitaminD-HealthProfessional/" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">Available online</a>. Last accessed April 7, 2017.</div></li><li><div class="bk_ref" id="CDR0000719335_rl_357_3">Hsu JW, Yasmin-Karim S, King MR, et al.: Suppression of prostate cancer cell rolling and adhesion to endothelium by 1α,25-dihydroxyvitamin D3. Am J Pathol 178 (2): 872-80, 2011. [<a href="/pmc/articles/PMC3069912/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3069912</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/21281819" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21281819</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_357_4">Gregory KJ, Zhao B, Bielenberg DR, et al.: Vitamin D binding protein-macrophage activating factor directly inhibits proliferation, migration, and uPAR expression of prostate cancer cells. PLoS One 5 (10): e13428, 2010. [<a href="/pmc/articles/PMC2956649/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2956649</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/20976141" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20976141</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_357_5">Karlsson S, Olausson J, Lundh D, et al.: Vitamin D and prostate cancer: the role of membrane initiated signaling pathways in prostate cancer progression. J Steroid Biochem Mol Biol 121 (1-2): 413-6, 2010. [<a href="https://pubmed.ncbi.nlm.nih.gov/20398754" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20398754</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_357_6">Mordan-McCombs S, Brown T, Wang WL, et al.: Tumor progression in the LPB-Tag transgenic model of prostate cancer is altered by vitamin D receptor and serum testosterone status. J Steroid Biochem Mol Biol 121 (1-2): 368-71, 2010. [<a href="/pmc/articles/PMC4211603/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4211603</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/20347977" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20347977</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_357_7">Zheng Y, Zhou H, Ooi LL, et al.: Vitamin D deficiency promotes prostate cancer growth in bone. Prostate 71 (9): 1012-21, 2011. [<a href="https://pubmed.ncbi.nlm.nih.gov/21541977" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21541977</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_357_8">Ajibade AA, Kirk JS, Karasik E, et al.: Early growth inhibition is followed by increased metastatic disease with vitamin D (calcitriol) treatment in the TRAMP model of prostate cancer. PLoS One 9 (2): e89555, 2014. [<a href="/pmc/articles/PMC3935875/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3935875</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/24586868" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24586868</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_357_9">Ahn J, Peters U, Albanes D, et al.: Serum vitamin D concentration and prostate cancer risk: a nested case-control study. J Natl Cancer Inst 100 (11): 796-804, 2008. [<a href="/pmc/articles/PMC3703748/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3703748</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/18505967" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18505967</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_357_10">Kimura M, Rabbani Z, Mouraviev V, et al.: Role of vitamin D(3) as a sensitizer to cryoablation in a murine prostate cancer model: preliminary in vivo study. Urology 76 (3): 764.e14-20, 2010. [<a href="https://pubmed.ncbi.nlm.nih.gov/20599255" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20599255</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_357_11">Santucci KL, Snyder KK, Baust JM, et al.: Use of 1,25α dihydroxyvitamin D3 as a cryosensitizing agent in a murine prostate cancer model. Prostate Cancer Prostatic Dis 14 (2): 97-104, 2011. [<a href="/pmc/articles/PMC3094482/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3094482</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/21221127" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21221127</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_357_12">Gavrilov V, Leibovich Y, Ariad S, et al.: A combined pretreatment of 1,25-dihydroxyvitamin D3 and sodium valproate enhances the damaging effect of ionizing radiation on prostate cancer cells. J Steroid Biochem Mol Biol 121 (1-2): 391-4, 2010. [<a href="https://pubmed.ncbi.nlm.nih.gov/20214985" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20214985</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_357_13">Choo CS, Mamedov A, Chung M, et al.: Vitamin D insufficiency is common in patients with nonmetastatic prostate cancer. Nutr Res 31 (1): 21-6, 2011. [<a href="https://pubmed.ncbi.nlm.nih.gov/21310302" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21310302</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_357_14">Fang F, Kasperzyk JL, Shui I, et al.: Prediagnostic plasma vitamin D metabolites and mortality among patients with prostate cancer. PLoS One 6 (4): e18625, 2011. [<a href="/pmc/articles/PMC3071841/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3071841</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/21494639" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21494639</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_357_15">Tretli S, Hernes E, Berg JP, et al.: Association between serum 25(OH)D and death from prostate cancer. Br J Cancer 100 (3): 450-4, 2009. [<a href="/pmc/articles/PMC2658536/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2658536</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19156140" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19156140</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_357_16">Albanes D, Mondul AM, Yu K, et al.: Serum 25-hydroxy vitamin D and prostate cancer risk in a large nested case-control study. Cancer Epidemiol Biomarkers Prev 20 (9): 1850-60, 2011. [<a href="/pmc/articles/PMC3188814/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3188814</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/21784952" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21784952</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_357_17">Xu Y, Shao X, Yao Y, et al.: Positive association between circulating 25-hydroxyvitamin D levels and prostate cancer risk: new findings from an updated meta-analysis. J Cancer Res Clin Oncol 140 (9): 1465-77, 2014. [<a href="https://pubmed.ncbi.nlm.nih.gov/24838848" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24838848</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_357_18">Murphy AB, Nyame Y, Martin IK, et al.: Vitamin D deficiency predicts prostate biopsy outcomes. Clin Cancer Res 20 (9): 2289-99, 2014. [<a href="/pmc/articles/PMC4104275/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4104275</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/24789033" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24789033</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_357_19">Kristal AR, Till C, Song X, et al.: Plasma vitamin D and prostate cancer risk: results from the Selenium and Vitamin E Cancer Prevention Trial. Cancer Epidemiol Biomarkers Prev 23 (8): 1494-504, 2014. [<a href="/pmc/articles/PMC4119495/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4119495</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/24732629" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24732629</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_357_20">Nyame YA, Murphy AB, Bowen DK, et al.: Associations Between Serum Vitamin D and Adverse Pathology in Men Undergoing Radical Prostatectomy. J Clin Oncol 34 (12): 1345-9, 2016. [<a href="/pmc/articles/PMC4872348/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4872348</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/26903577" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26903577</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_357_21">Vieth R, Choo R, Deboer L, et al.: Rise in prostate-specific antigen in men with untreated low-grade prostate cancer is slower during spring-summer. Am J Ther 13 (5): 394-9, 2006 Sep-Oct. [<a href="https://pubmed.ncbi.nlm.nih.gov/16988533" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16988533</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_357_22">Gilbert R, Metcalfe C, Oliver SE, et al.: Life course sun exposure and risk of prostate cancer: population-based nested case-control study and meta-analysis. Int J Cancer 125 (6): 1414-23, 2009. [<a href="/pmc/articles/PMC2873563/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2873563</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19444909" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19444909</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_357_23">Schwartz GG, Hanchette CL: UV, latitude, and spatial trends in prostate cancer mortality: all sunlight is not the same (United States). Cancer Causes Control 17 (8): 1091-101, 2006. [<a href="https://pubmed.ncbi.nlm.nih.gov/16933060" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16933060</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_357_24">Grant WB: An ecological study of cancer incidence and mortality rates in France with respect to latitude, an index for vitamin D production. Dermatoendocrinol 2 (2): 62-7, 2010. [<a href="/pmc/articles/PMC3081677/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3081677</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/21547101" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21547101</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_357_25">Hendrickson WK, Flavin R, Kasperzyk JL, et al.: Vitamin D receptor protein expression in tumor tissue and prostate cancer progression. J Clin Oncol 29 (17): 2378-85, 2011. [<a href="/pmc/articles/PMC3107752/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3107752</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/21537045" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21537045</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_357_26">Chen L, Davey Smith G, Evans DM, et al.: Genetic variants in the vitamin d receptor are associated with advanced prostate cancer at diagnosis: findings from the prostate testing for cancer and treatment study and a systematic review. Cancer Epidemiol Biomarkers Prev 18 (11): 2874-81, 2009. [<a href="https://pubmed.ncbi.nlm.nih.gov/19861519" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19861519</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_357_27">Holt SK, Kwon EM, Koopmeiners JS, et al.: Vitamin D pathway gene variants and prostate cancer prognosis. Prostate 70 (13): 1448-60, 2010. [<a href="/pmc/articles/PMC2927712/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2927712</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/20687218" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20687218</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_357_28">Gilbert R, Bonilla C, Metcalfe C, et al.: Associations of vitamin D pathway genes with circulating 25-hydroxyvitamin-D, 1,25-dihydroxyvitamin-D, and prostate cancer: a nested case-control study. Cancer Causes Control 26 (2): 205-18, 2015. [<a href="/pmc/articles/PMC4298668/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4298668</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/25488826" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25488826</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_357_29">Shui IM, Mondul AM, Lindström S, et al.: Circulating vitamin D, vitamin D-related genetic variation, and risk of fatal prostate cancer in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium. Cancer 121 (12): 1949-56, 2015. [<a href="/pmc/articles/PMC4457645/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4457645</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/25731953" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25731953</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_357_30">Huncharek M, Muscat J, Kupelnick B: Dairy products, dietary calcium and vitamin D intake as risk factors for prostate cancer: a meta-analysis of 26,769 cases from 45 observational studies. Nutr Cancer 60 (4): 421-41, 2008. [<a href="https://pubmed.ncbi.nlm.nih.gov/18584476" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18584476</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_357_31">Gilbert R, Martin RM, Beynon R, et al.: Associations of circulating and dietary vitamin D with prostate cancer risk: a systematic review and dose-response meta-analysis. Cancer Causes Control 22 (3): 319-40, 2011. [<a href="https://pubmed.ncbi.nlm.nih.gov/21203822" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21203822</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_357_32">Srinivas S, Feldman D: A phase II trial of calcitriol and naproxen in recurrent prostate cancer. Anticancer Res 29 (9): 3605-10, 2009. [<a href="https://pubmed.ncbi.nlm.nih.gov/19667155" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19667155</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_357_33">Chadha MK, Tian L, Mashtare T, et al.: Phase 2 trial of weekly intravenous 1,25 dihydroxy cholecalciferol (calcitriol) in combination with dexamethasone for castration-resistant prostate cancer. Cancer 116 (9): 2132-9, 2010. [<a href="https://pubmed.ncbi.nlm.nih.gov/20166215" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20166215</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_357_34">Newsom-Davis TE, Kenny LM, Ngan S, et al.: The promiscuous receptor. BJU Int 104 (9): 1204-7, 2009. [<a href="https://pubmed.ncbi.nlm.nih.gov/19426197" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19426197</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_357_35">Standing Committee on the Scientific Evaluation of Dietary Reference Intakes: Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride. Washington, DC: National Academy Press, 1997. Also <a href="https://www.nap.edu/read/5776/chapter/1#R1" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">available online</a>. Last accessed April 7, 2017. [<a href="https://pubmed.ncbi.nlm.nih.gov/23115811" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23115811</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_357_36">Kennedy DA, Cooley K, Skidmore B, et al.: Vitamin d: pharmacokinetics and safety when used in conjunction with the pharmaceutical drugs used in cancer patients: a systematic review. Cancers (Basel) 5 (1): 255-80, 2013. [<a href="/pmc/articles/PMC3730309/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3730309</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/24216707" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24216707</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_357_37">Petrioli R, Pascucci A, Francini E, et al.: Weekly high-dose calcitriol and docetaxel in patients with metastatic hormone-refractory prostate cancer previously exposed to docetaxel. BJU Int 100 (4): 775-9, 2007. [<a href="https://pubmed.ncbi.nlm.nih.gov/17535276" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17535276</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_357_38">Tiffany NM, Ryan CW, Garzotto M, et al.: High dose pulse calcitriol, docetaxel and estramustine for androgen independent prostate cancer: a phase I/II study. J Urol 174 (3): 888-92, 2005. [<a href="https://pubmed.ncbi.nlm.nih.gov/16093981" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16093981</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_357_39">Beer TM, Eilers KM, Garzotto M, et al.: Weekly high-dose calcitriol and docetaxel in metastatic androgen-independent prostate cancer. J Clin Oncol 21 (1): 123-8, 2003. [<a href="https://pubmed.ncbi.nlm.nih.gov/12506180" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12506180</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_357_40">Beer TM, Ryan CW, Venner PM, et al.: Double-blinded randomized study of high-dose calcitriol plus docetaxel compared with placebo plus docetaxel in androgen-independent prostate cancer: a report from the ASCENT Investigators. J Clin Oncol 25 (6): 669-74, 2007. [<a href="https://pubmed.ncbi.nlm.nih.gov/17308271" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17308271</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_357_41">Fakih MG, Trump DL, Muindi JR, et al.: A phase I pharmacokinetic and pharmacodynamic study of intravenous calcitriol in combination with oral gefitinib in patients with advanced solid tumors. Clin Cancer Res 13 (4): 1216-23, 2007. [<a href="https://pubmed.ncbi.nlm.nih.gov/17317832" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17317832</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_357_42">Muindi JR, Peng Y, Potter DM, et al.: Pharmacokinetics of high-dose oral calcitriol: results from a phase 1 trial of calcitriol and paclitaxel. Clin Pharmacol Ther 72 (6): 648-59, 2002. [<a href="https://pubmed.ncbi.nlm.nih.gov/12496746" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12496746</span></a>]</div></li></ol></div></div><div id="CDR0000719335__328"><h2 id="_CDR0000719335__328_">Vitamin E</h2><div id="CDR0000719335__329"><h3>Overview</h3><ul id="CDR0000719335__330"><li class="half_rhythm"><div>Most <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000373932/" class="def">dietary</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045023/" class="def">vitamin E</a> comes from gamma-tocopherol. Food sources of vitamin E include vegetable oil, nuts, and egg yolks.</div></li><li class="half_rhythm"><div>Research suggests that vitamin E may protect against a number of <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045641/" class="def">chronic</a> diseases, such as <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000748137/" class="def">cardiovascular disease</a>. </div></li><li class="half_rhythm"><div>Studies suggest that <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000691423/" class="def">alpha-tocopherol</a>–associated <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046092/" class="def">protein</a> (TAP) may have capabilities as a <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046657/" class="def">tumor suppressor</a> in <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000445079/" class="def">prostate cancer</a>.</div></li><li class="half_rhythm"><div>The Selenium and Vitamin E Cancer Prevention Trial (SELECT), a large <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044939/" class="def">multicenter</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045961/" class="def">clinical trial</a>, was initiated by the <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044268/" class="def">National Institutes of Health</a> (NIH) in 2001 to examine the effects of <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045113/" class="def">selenium</a> and/or vitamin E on the development of prostate cancer.</div></li><li class="half_rhythm"><div>In 2011, updated results from SELECT showed that men who took vitamin E alone had a 17% increase in prostate cancer risk compared with men who took placebo.</div></li><li class="half_rhythm"><div>In 2014, an analysis of SELECT results showed that men who had high selenium status at <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000467830/" class="def">baseline</a> and who were randomly assigned to receive selenium <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045916/" class="def">supplementation</a> had an increased risk of <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000386205/" class="def">high-grade</a> prostate cancer, but vitamin E supplementation had no effect among men with high selenium status.</div></li></ul></div><div id="CDR0000719335__331"><h3>General Information and History</h3><p id="CDR0000719335__332">Vitamin E was discovered in 1922 as a factor essential for reproduction.[<a class="bk_pop" href="#CDR0000719335_rl_328_1">1</a>]</p><p id="CDR0000719335__333">Vitamin E occurs in eight different forms: four tocopherols (alpha-, beta-, gamma-, and sigma-) and four tocotrienols (alpha-, beta-, gamma-, and sigma-).[<a class="bk_pop" href="#CDR0000719335_rl_328_2">2</a>] Compared with other tocopherols, alpha-tocopherol (the form of vitamin E commonly found in dietary supplements) is the most abundant in the body and the most biologically active. Most dietary vitamin E comes from gamma-tocopherol. Food sources of vitamin E include vegetable oil, nuts, and egg yolks.[<a class="bk_pop" href="#CDR0000719335_rl_328_3">3</a>]</p><p id="CDR0000719335__334">The <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044225/" class="def">bioavailability</a> of vitamin E depends on a number of factors, such as the food matrix containing vitamin E (e.g., low- or high-fat food).[<a class="bk_pop" href="#CDR0000719335_rl_328_4">4</a>] Vitamin E is delivered to <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046683/" class="def">tissues</a> by high- and low-density lipoproteins (HDL and LDL, respectively). Delivery by LDL occurs via an endocytic pathway, while the protein’s <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044749/" class="def">ATP</a>-binding cassette, subfamily 1 and scavenger <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044958/" class="def">receptor</a> class B type 1 (SR-BI) are involved in HDL vitamin E transport.[<a class="bk_pop" href="#CDR0000719335_rl_328_5">5</a>]</p><p id="CDR0000719335__335">Research suggests that vitamin E may protect against a number of chronic diseases, such as cardiovascular disease.[<a class="bk_pop" href="#CDR0000719335_rl_328_1">1</a>] Many of vitamin E’s health benefits have been ascribed to its actions as a powerful <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000043997/" class="def">antioxidant</a>; as with other antioxidants, vitamin E protects <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046476/" class="def">cell</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046294/" class="def">membranes</a> by interfering with reactions that would form <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046068/" class="def">lipid</a> hydroperoxide products.[<a class="bk_pop" href="#CDR0000719335_rl_328_5">5</a>] Vitamin E also has nonantioxidant functions: it has been shown to <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000390300/" class="def">modulate</a> signaling pathways and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000537335/" class="def">gene expression</a>.[<a class="bk_pop" href="#CDR0000719335_rl_328_3">3</a>]</p></div><div id="CDR0000719335__336"><h3>Human Studies</h3><div id="CDR0000719335__337"><h4>Epidemiologic studies</h4><p id="CDR0000719335__338">The NIH-AARP Diet and Health Study was initiated to examine whether supplemental vitamin E and dietary tocopherol intakes may prevent prostate cancer. Participants in the study completed food-frequency questionnaires and were monitored for 5 years. No association between vitamin E supplements and prostate cancer risk was found. However, a reduction in the risk of advanced prostate cancer was observed with high intakes of gamma-tocopherol.[<a class="bk_pop" href="#CDR0000719335_rl_328_6">6</a>]</p><p id="CDR0000719335__339">In a 2010 study, levels of <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044573/" class="def">trace elements</a> and vitamin E were measured in prostate cancer patients. Prostate cancer patients had significantly lower levels of <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045839/" class="def">plasma</a> vitamin E than did healthy controls. In addition, there was an inverse association between <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046540/" class="def">prostate-specific antigen</a> levels and plasma vitamin E.[<a class="bk_pop" href="#CDR0000719335_rl_328_7">7</a>]</p><p id="CDR0000719335__340">Studies suggest that alpha-tocopherol–associated protein (TAP) may have capabilities as a <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046634/" class="def">tumor</a> suppressor in prostate cancer. In a 2007 study, prostate cancer specimens, which had been obtained from <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046549/" class="def">radical prostatectomy</a>, were examined for TAP expression. Results showed reduced TAP expression in prostate cancer <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046683/" class="def">tissue</a> and lower levels of TAP were associated with higher <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000686244/" class="def">clinical stage</a> and larger tumor size.[<a class="bk_pop" href="#CDR0000719335_rl_328_8">8</a>]</p><p id="CDR0000719335__341">A study published in 2011 examined <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044088/" class="def">serum</a> alpha-tocopherol and supplemental vitamin E intake with sex <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000613764/" class="def">steroid</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045713/" class="def">hormones</a> in participants in the Third National Health and Nutrition Examination Survey (NHANES III). Results showed an inverse association between serum alpha-tocopherol levels and sex steroid hormones, but only in smokers.[<a class="bk_pop" href="#CDR0000719335_rl_328_9">9</a>]</p><p id="CDR0000719335__342">Serum alpha-tocopherol and gamma-tocopherol levels and prostate cancer risk were examined in participants in the Prostate, Lung, Colorectal and Ovarian (PLCO) Screening Trial. An inverse relationship was observed between alpha-tocopherol levels and prostate cancer, but only in current and recently former smokers.[<a class="bk_pop" href="#CDR0000719335_rl_328_10">10</a>] A <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000691484/" class="def">meta-analysis</a> of nine nested <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000348989/" class="def">case-control studies</a>, representing approximately 370,000 men from several countries, also found an inverse relationship between blood alpha-tocopherol levels and prostate cancer risk, but in all patients studied rather than limited to a smoking subset.[<a class="bk_pop" href="#CDR0000719335_rl_328_11">11</a>] No association was seen with gamma-tocopherol levels in this analysis. The risk of prostate cancer decreased by 21% for every 25 mg/L increase in blood alpha-tocopherol levels.</p><p id="CDR0000719335__610">The North Carolina-Louisiana Prostate Cancer Project investigated racial and geographic differences in prostate cancer <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046053/" class="def">aggressiveness</a>.[<a class="bk_pop" href="#CDR0000719335_rl_328_12">12</a>] The effects of food intake of tocopherols, vitamin E supplementation, and adipose tissue <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045618/" class="def">biomarkers</a> of tocopherol were studied. In 1,023 African American men and 1,079 white men studied with incident prostate cancer, inverse associations were observed between dietary sources of tocopherol and prostate cancer aggressiveness that were <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044167/" class="def">statistically significant</a> in white men but not in African American men.</p></div><div id="CDR0000719335__343"><h4>Intervention Studies</h4><p id="CDR0000719335__344">The Physicians’ Health Study II investigated whether <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000439435/" class="def">vitamin C</a> or vitamin E prevents prostate cancer and other <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045333/" class="def">cancers</a> in men. Participants in the study were randomly assigned to receive vitamin E (400 <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044764/" class="def">IU</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000462950/" class="def">synthetic</a> alpha-tocopherol taken every other day) and/or vitamin C (500 <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044213/" class="def">mg</a> synthetic <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000439436/" class="def">ascorbic acid</a> taken daily) supplements and were monitored for an average of 8 years. The overall rates of prostate cancer were very similar in the vitamin E supplement and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046688/" class="def">placebo</a> groups, suggesting that vitamin E may not prevent prostate cancer. Furthermore, vitamin E did not have an effect on total cancer or <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000496502/" class="def">mortality</a> in these participants.[<a class="bk_pop" href="#CDR0000719335_rl_328_13">13</a>]</p><p id="CDR0000719335__345">Although not primarily designed for this purpose, the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study has been a resource for researchers investigating prostate cancer and vitamin E.[<a class="bk_pop" href="#CDR0000719335_rl_328_14">14</a>] A long <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044671/" class="def">follow-up</a> study of participants in the ATBC Study was conducted. Baseline serum alpha-tocopherol levels and dietary intake of vitamin E had been assessed and participants were monitored for up to 19 years. Findings revealed that while there was no association between dietary vitamin E levels and prostate cancer risk, higher serum alpha-tocopherol levels may be associated with a decreased risk for developing advanced prostate cancer.[<a class="bk_pop" href="#CDR0000719335_rl_328_15">15</a>] In a 2009 study, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000270735/" class="def">blood</a> samples obtained from participants in the ATBC Study were analyzed and genotyped. Results showed that <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046391/" class="def">genetic</a> variations in the <i>TTPA</i> and <i>SEC14L2</i>
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<a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000045693/" class="def">genes</a> were associated with serum alpha-tocopherol but did not directly affect prostate cancer risk. However, results suggested that <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000044805/" class="def">polymorphisms</a> in <i>SEC14L2</i> may influence the effect of alpha-tocopherol supplementation on prostate cancer risk.[<a class="bk_pop" href="#CDR0000719335_rl_328_16">16</a>] One study also focused on the ATBC Study and investigated whether serum alpha-tocopherol levels <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000460124/" class="def">affected</a> survival time in men <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046450/" class="def">diagnosed</a> with prostate cancer. Serum alpha-tocopherol levels were assessed at baseline and 3 years later. Higher serum alpha-tocopherol levels, at both baseline and the 3-year point, were associated with improved prostate cancer survival.[<a class="bk_pop" href="#CDR0000719335_rl_328_17">17</a>]</p><p id="CDR0000719335__346">A 2011 study examined links between serum alpha- and gamma-tocopherols and risk of prostate cancer among participants in the Carotene and Retinol Efficacy Trial (CARET). CARET was a randomized, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044840/" class="def">placebo-controlled</a> study that investigated whether daily supplementation of <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045328/" class="def">beta-carotene</a> and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046058/" class="def">retinyl palmitate</a> would reduce the risk of <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000445043/" class="def">lung cancer</a> in heavy smokers and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046528/" class="def">asbestos</a>-exposed workers. Results indicated that among current smokers, higher levels of serum alpha- and gamma-tocopherols were associated with reduced risk of aggressive prostate cancer. In addition, findings suggested there may be an interaction between myeloperoxidase (MGO) G-463A <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000660739/" class="def">genotype</a>, serum alpha-tocopherol level, and prostate cancer risk. Specific genotypes were associated with increased prostate cancer risk in subjects with low levels of serum alpha-tocopherol, while those same genotypes along with higher levels of alpha-tocopherol were associated with reduced risk of prostate cancer.[<a class="bk_pop" href="#CDR0000719335_rl_328_18">18</a>]</p><div id="CDR0000719335__347"><h5>The Selenium and Vitamin E Cancer Prevention Trial (SELECT)</h5><p id="CDR0000719335__348">On the basis of findings from earlier studies,[<a class="bk_pop" href="#CDR0000719335_rl_328_14">14</a>,<a class="bk_pop" href="#CDR0000719335_rl_328_19">19</a>] the SELECT, a large <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044939/" class="def">multicenter</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045961/" class="def">clinical trial</a>, was initiated by the NIH in 2001 to examine the effects of selenium and/or vitamin E on the development of prostate cancer. SELECT was a <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045833/" class="def">phase III</a>, randomized, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045673/" class="def">double-blind</a>, placebo-controlled, population-based trial.[<a class="bk_pop" href="#CDR0000719335_rl_328_20">20</a>] More than 35,000 men, aged 50 years or older, from more than 400 study sites in the United States, Canada, and Puerto Rico were randomly assigned to receive vitamin E (all-rac-alpha-tocopherol <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000655020/" class="def">acetate</a>, 400 IU daily) and a placebo, selenium (L-selenomethionine, 200 µg daily) and a placebo, vitamin E and selenium, or two <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046688/" class="def">placebos</a> daily for 7 to 12 years. The <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044163/" class="def">primary endpoint</a> of the clinical trial was <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046145/" class="def">incidence</a> of prostate cancer.[<a class="bk_pop" href="#CDR0000719335_rl_328_20">20</a>]</p><p id="CDR0000719335__349">Initial results of SELECT were published in 2009. There were no statistically significant differences in rates of prostate cancer in the four groups. In the vitamin E–alone group, there was a nonsignificant increase in rates of prostate cancer (<i>P</i> = .06); in the selenium–alone group, there was a nonsignificant increase in incidence of <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044129/" class="def">diabetes mellitus</a> (<i>P</i> = .16). On the basis of those findings, the data and safety <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000454803/" class="def">monitoring</a> committee recommended that participants stop taking the study supplements.[<a class="bk_pop" href="#CDR0000719335_rl_328_21">21</a>]</p><p id="CDR0000719335__350">Updated results were published in 2011. When compared with placebo, the rate of prostate cancer detection was significantly greater in the vitamin E–alone group (<i>P</i> = .008) and represented a 17% increase in prostate cancer risk. There was also greater incidence of prostate cancer in men who had taken selenium than in men who had taken placebo, but those differences were not statistically significant.[<a class="bk_pop" href="#CDR0000719335_rl_328_22">22</a>]</p><p id="CDR0000719335__464">Toenail selenium levels were <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044528/" class="def">assayed</a> in a two-case <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000285673/" class="def">cohort study</a> of a subset of SELECT participants. Vitamin E supplementation (alone) had no effect among men with high selenium status at baseline but increased the risks of total (63%; <i>P</i> = .02), <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000386213/" class="def">low-grade</a> (46%; <i>P</i> = .09), and high-grade (111%; <i>P</i> = .008) prostate cancer among men with lower baseline selenium status. The authors concluded that men older than 55 years should avoid supplementation with either vitamin E or selenium at doses exceeding dietary recommendations.[<a class="bk_pop" href="#CDR0000719335_rl_328_23">23</a>] In a case-cohort analysis of 1,434 men in the SELECT who underwent analysis of <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000458046/" class="def">single nucleotide polymorphisms</a> in 21 genes, investigators found support for the <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044209/" class="def">hypothesis</a> that genetic variation in selenium and vitamin E metabolism/transport genes may influence the risk of overall and high-grade prostate cancer and that selenium or vitamin E supplementation may modify an individual's response to those risks.[<a class="bk_pop" href="#CDR0000719335_rl_328_24">24</a>]</p><p id="CDR0000719335__351">The <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044664/" class="def">dose</a> and form of vitamin E used in SELECT may have contributed to the results. On the basis of the results of the ATBC Study, all-rac-alpha-tocopheryl acetate was the form of vitamin E used in SELECT. The dose used in SELECT (400 IU) was higher than that in the ATBC Study. SELECT researchers opted for the higher dose because it was found in vitamin supplements, there was evidence for benefits of higher doses (including reductions in Alzheimer’s disease and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000642152/" class="def">age-related macular degeneration</a>), and it was thought the higher dose would be more protective against prostate cancer than a lower dose.[<a class="bk_pop" href="#CDR0000719335_rl_328_25">25</a>] Following the results of SELECT, it has been posited that high levels of alpha-tocopherol may affect levels of gamma-tocopherol, another form of vitamin E that may have <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045487/" class="def">chemopreventive</a> effects.[<a class="bk_pop" href="#CDR0000719335_rl_328_26">26</a>] Another important difference between the ATBC Study and SELECT that may explain the findings was the smoking status of study participants. Participants in the ATBC Study were smokers, while 7.5% of SELECT participants used <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000439432/" class="def">tobacco</a> products.[<a class="bk_pop" href="#CDR0000719335_rl_328_27">27</a>]</p></div></div><div id="CDR0000719335__410"><h4>Current clinical trials</h4><p id="CDR0000719335__411">Check NCI’s list of cancer clinical trials for CAM clinical trials on <a href="https://www.cancer.gov/about-cancer/treatment/clinical-trials/search/results?protocolsearchid=12112455&vers=1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">vitamin E</a> that are actively enrolling patients.</p><p id="CDR0000719335__412">General information about clinical trials is also available from the <a href="https://www.cancer.gov/about-cancer/treatment/clinical-trials" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NCI website</a>.</p></div></div><div id="CDR0000719335__352"><h3>Adverse Effects</h3><p id="CDR0000719335__353">Alpha-tocopherols have been deemed Generally Recognized as Safe by the <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000454785/" class="def">U.S. Food and Drug Administration</a>.[<a class="bk_pop" href="#CDR0000719335_rl_328_28">28</a>]</p><p id="CDR0000719335__354">In the Physicians’ Health Study II, there were no significant adverse effects reported for <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046189/" class="def">gastrointestinal tract</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045022/" class="def">symptoms</a>, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000321374/" class="def">fatigue</a>, drowsiness, skin discoloration or rashes, or migraine. However, participants who took vitamin E (400 IU of alpha-tocopherol every other day) experienced a greater number of hemorrhagic strokes than did participants who took placebo.[<a class="bk_pop" href="#CDR0000719335_rl_328_13">13</a>] An increase in hemorrhagic strokes among participants in the vitamin E group (50 mg of alpha-tocopherol daily) also was noted in the ATBC Study.[<a class="bk_pop" href="#CDR0000719335_rl_328_14">14</a>]</p><p id="CDR0000719335__355">In the initial report of results from SELECT, there were no significant differences between incidences of less severe <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044922/" class="def">adverse effects</a> (e.g., <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044642/" class="def">alopecia</a>, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045667/" class="def">dermatitis</a>, and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000390302/" class="def">nausea</a>) experienced by the groups that received vitamin E (400 IU of all rac-alpha-tocopheryl acetate per day) and those experienced by the other treatment groups.[<a class="bk_pop" href="#CDR0000719335_rl_328_21">21</a>] Follow-up analysis of SELECT participants revealed an increased risk of prostate cancer among men in the vitamin E–alone group.[<a class="bk_pop" href="#CDR0000719335_rl_328_22">22</a>]</p></div><div id="CDR0000719335_rl_328"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000719335_rl_328_1">Pekmezci D: Vitamin E and immunity. Vitam Horm 86: 179-215, 2011. [<a href="https://pubmed.ncbi.nlm.nih.gov/21419272" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21419272</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_328_2">Crispen PL, Uzzo RG, Golovine K, et al.: Vitamin E succinate inhibits NF-kappaB and prevents the development of a metastatic phenotype in prostate cancer cells: implications for chemoprevention. Prostate 67 (6): 582-90, 2007. [<a href="https://pubmed.ncbi.nlm.nih.gov/17262802" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17262802</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_328_3">Ni J, Yeh S: The roles of alpha-vitamin E and its analogues in prostate cancer. Vitam Horm 76: 493-518, 2007. [<a href="https://pubmed.ncbi.nlm.nih.gov/17628187" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17628187</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_328_4">Mustacich DJ, Bruno RS, Traber MG: Vitamin E. Vitam Horm 76: 1-21, 2007. [<a href="https://pubmed.ncbi.nlm.nih.gov/17628169" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17628169</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_328_5">Traber MG: Vitamin E. In: Coates PM, Betz JM, Blackman MR, et al., eds.: Encyclopedia of Dietary Supplements. 2nd ed. New York, NY: Informa Healthcare, 2010, pp 841-50.</div></li><li><div class="bk_ref" id="CDR0000719335_rl_328_6">Wright ME, Weinstein SJ, Lawson KA, et al.: Supplemental and dietary vitamin E intakes and risk of prostate cancer in a large prospective study. Cancer Epidemiol Biomarkers Prev 16 (6): 1128-35, 2007. [<a href="https://pubmed.ncbi.nlm.nih.gov/17548674" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17548674</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_328_7">Adaramoye OA, Akinloye O, Olatunji IK: Trace elements and vitamin E status in Nigerian patients with prostate cancer. Afr Health Sci 10 (1): 2-8, 2010. [<a href="/pmc/articles/PMC2895796/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2895796</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/20811517" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20811517</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_328_8">Wen XQ, Li XJ, Su ZL, et al.: Reduced expression of alpha-tocopherol-associated protein is associated with tumor cell proliferation and the increased risk of prostate cancer recurrence. Asian J Androl 9 (2): 206-12, 2007. [<a href="https://pubmed.ncbi.nlm.nih.gov/17334589" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17334589</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_328_9">Mondul AM, Rohrmann S, Menke A, et al.: Association of serum α-tocopherol with sex steroid hormones and interactions with smoking: implications for prostate cancer risk. Cancer Causes Control 22 (6): 827-36, 2011. [<a href="/pmc/articles/PMC3499970/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3499970</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/21424597" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21424597</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_328_10">Weinstein SJ, Peters U, Ahn J, et al.: Serum α-tocopherol and γ-tocopherol concentrations and prostate cancer risk in the PLCO Screening Trial: a nested case-control study. PLoS One 7 (7): e40204, 2012. [<a href="/pmc/articles/PMC3390343/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3390343</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/22792240" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22792240</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_328_11">Cui R, Liu ZQ, Xu Q: Blood α-tocopherol, γ-tocopherol levels and risk of prostate cancer: a meta-analysis of prospective studies. PLoS One 9 (3): e93044, 2014. [<a href="/pmc/articles/PMC3965522/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3965522</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/24667740" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24667740</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_328_12">Antwi SO, Steck SE, Su LJ, et al.: Dietary, supplement, and adipose tissue tocopherol levels in relation to prostate cancer aggressiveness among African and European Americans: The North Carolina-Louisiana Prostate Cancer Project (PCaP). Prostate 75 (13): 1419-35, 2015. [<a href="/pmc/articles/PMC5072779/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5072779</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/26053590" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26053590</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_328_13">Gaziano JM, Glynn RJ, Christen WG, et al.: Vitamins E and C in the prevention of prostate and total cancer in men: the Physicians' Health Study II randomized controlled trial. JAMA 301 (1): 52-62, 2009. [<a href="/pmc/articles/PMC2774210/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2774210</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19066368" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19066368</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_328_14">The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. N Engl J Med 330 (15): 1029-35, 1994. [<a href="https://pubmed.ncbi.nlm.nih.gov/8127329" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8127329</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_328_15">Weinstein SJ, Wright ME, Lawson KA, et al.: Serum and dietary vitamin E in relation to prostate cancer risk. Cancer Epidemiol Biomarkers Prev 16 (6): 1253-9, 2007. [<a href="https://pubmed.ncbi.nlm.nih.gov/17548693" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17548693</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_328_16">Wright ME, Peters U, Gunter MJ, et al.: Association of variants in two vitamin e transport genes with circulating vitamin e concentrations and prostate cancer risk. Cancer Res 69 (4): 1429-38, 2009. [<a href="/pmc/articles/PMC2644342/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2644342</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19190344" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19190344</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_328_17">Watters JL, Gail MH, Weinstein SJ, et al.: Associations between alpha-tocopherol, beta-carotene, and retinol and prostate cancer survival. Cancer Res 69 (9): 3833-41, 2009. [<a href="/pmc/articles/PMC2787239/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2787239</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19383902" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19383902</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_328_18">Cheng TY, Barnett MJ, Kristal AR, et al.: Genetic variation in myeloperoxidase modifies the association of serum α-tocopherol with aggressive prostate cancer among current smokers. J Nutr 141 (9): 1731-7, 2011. [<a href="/pmc/articles/PMC3735918/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3735918</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/21795425" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21795425</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_328_19">Clark LC, Combs GF Jr, Turnbull BW, et al.: Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin. A randomized controlled trial. Nutritional Prevention of Cancer Study Group. JAMA 276 (24): 1957-63, 1996. [<a href="https://pubmed.ncbi.nlm.nih.gov/8971064" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8971064</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_328_20">Klein EA: Selenium and vitamin E cancer prevention trial. Ann N Y Acad Sci 1031: 234-41, 2004. [<a href="https://pubmed.ncbi.nlm.nih.gov/15753149" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15753149</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_328_21">Lippman SM, Klein EA, Goodman PJ, et al.: Effect of selenium and vitamin E on risk of prostate cancer and other cancers: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA 301 (1): 39-51, 2009. [<a href="/pmc/articles/PMC3682779/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3682779</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19066370" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19066370</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_328_22">Klein EA, Thompson IM Jr, Tangen CM, et al.: Vitamin E and the risk of prostate cancer: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA 306 (14): 1549-56, 2011. [<a href="/pmc/articles/PMC4169010/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4169010</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/21990298" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21990298</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_328_23">Kristal AR, Darke AK, Morris JS, et al.: Baseline selenium status and effects of selenium and vitamin e supplementation on prostate cancer risk. J Natl Cancer Inst 106 (3): djt456, 2014. [<a href="/pmc/articles/PMC3975165/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3975165</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/24563519" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24563519</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_328_24">Chan JM, Darke AK, Penney KL, et al.: Selenium- or Vitamin E-Related Gene Variants, Interaction with Supplementation, and Risk of High-Grade Prostate Cancer in SELECT. Cancer Epidemiol Biomarkers Prev 25 (7): 1050-8, 2016. [<a href="/pmc/articles/PMC5086806/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5086806</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/27197287" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 27197287</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_328_25">Lippman SM, Goodman PJ, Klein EA, et al.: Designing the Selenium and Vitamin E Cancer Prevention Trial (SELECT). J Natl Cancer Inst 97 (2): 94-102, 2005. [<a href="https://pubmed.ncbi.nlm.nih.gov/15657339" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15657339</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_328_26">Ledesma MC, Jung-Hynes B, Schmit TL, et al.: Selenium and vitamin E for prostate cancer: post-SELECT (Selenium and Vitamin E Cancer Prevention Trial) status. Mol Med 17 (1-2): 134-43, 2011 Jan-Feb. [<a href="/pmc/articles/PMC3022975/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3022975</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/20882260" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20882260</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_328_27">Dunn BK, Richmond ES, Minasian LM, et al.: A nutrient approach to prostate cancer prevention: The Selenium and Vitamin E Cancer Prevention Trial (SELECT). Nutr Cancer 62 (7): 896-918, 2010. [<a href="https://pubmed.ncbi.nlm.nih.gov/20924966" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20924966</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_328_28">Select Committee on GRAS Substances (SCOGS) Opinion: alpha-Tocopherols. Silver Spring, Md: Food and Drug Administration, 2013. <a href="https://www.fda.gov/Food/IngredientsPackagingLabeling/GRAS/SCOGS/ucm260987.htm" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">Available online</a>. Last accessed April 7, 2017.</div></li></ol></div></div><div id="CDR0000719335__485"><h2 id="_CDR0000719335__485_">Multicomponent Therapies</h2><div id="CDR0000719335__486"><h3>Pomi-T (Pomegranate, Green Tea, Broccoli, and Turmeric)</h3><p id="CDR0000719335__487">In a <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044840/" class="def">placebo-controlled</a>, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045673/" class="def">double-blind</a>, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045858/" class="def">randomized</a> study, 199 men with <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045754/" class="def">localized</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000445079/" class="def">prostate cancer</a> were randomly assigned to either a food supplement, Pomi-T, or <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046688/" class="def">placebo</a> (2:1) for 6 months.[<a class="bk_pop" href="#CDR0000719335_rl_485_1">1</a>] Pomi-T contained 100 <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044213/" class="def">mg</a> each of <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000321386/" class="def">pomegranate</a> whole fruit powder, broccoli powder, and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000463050/" class="def">turmeric</a> powder; and 20 mg of <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000389271/" class="def">green tea extract</a> (equivalent to 100 mg of tea). The <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000463714/" class="def">herbal</a> ingredients in this supplement were raw, dry, powdered plant materials that were not <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000643008/" class="def">chemically</a> standardized. Chemical standardization is widely performed with herbal <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000407760/" class="def">extracts</a>, as a means of enhancing the reproducibility of studies with herbal <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000373932/" class="def">dietary supplements</a> via qualitative and quantitative chemical <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000390238/" class="def">analysis</a>. There were no <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000390271/" class="def">significant</a> differences in age or <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045696/" class="def">Gleason score</a> between the groups. Forty percent of the patients had rising <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046540/" class="def">prostate-specific antigen</a> (PSA) levels following <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045755/" class="def">local therapy</a> and 60% were on <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000616060/" class="def">active surveillance</a> (prelocal therapy). The study found a <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044941/" class="def">median</a> rise in PSA of 14.7% after 6 months in the Pomi-T group compared with a 78.5% median rise in PSA in the placebo group. The supplement was well tolerated with no significant increase in <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000444960/" class="def">adverse events</a> compared with placebo, although a trend was noted towards increased flatulence and loose <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046500/" class="def">bowels</a> in the supplement group.</p><p id="CDR0000719335__532">Important differences exist between pomegranate preparation and standardization. While dried fruit powder is commonly found in the marketplace, an equal amount of pomegranate fruit extract has a much higher content of <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000256573/" class="def">polyphenols</a> that are considered the bioactive constituents and can be used for the chemical standardization of preparations.</p></div><div id="CDR0000719335__660"><h3>Lycopene, Selenium, and Green Tea</h3><p id="CDR0000719335__661">In a randomized, double-blinded, placebo-controlled study of a supplement containing <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044909/" class="def">lycopene</a> (35 mg), <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045113/" class="def">selenium</a> (55 µg), and green tea <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000686469/" class="def">catechins</a> (600 mg) that was given for 6 months and targeted men with <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000386205/" class="def">high-grade</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044345/" class="def">prostatic intraepithelial neoplasia</a> (HGPIN) and/or atypical small acinar proliferation, a higher incidence of prostate cancer was seen on rebiopsy in men who received the supplement. Although the expected (or historical) rate of progression to prostate cancer is less than 20% (even at 1 year), more than 25.5% of this population of men had a diagnosis of prostate cancer at 6 months, which may be attributed to inadequate sampling and potentially missed cancers at <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000467830/" class="def">baseline</a>. A high percentage of positive biopsies raises the concern for cancers missed on baseline <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045164/" class="def">biopsy</a>, and thus, further study is warranted.[<a class="bk_pop" href="#CDR0000719335_rl_485_2">2</a>]</p></div><div id="CDR0000719335__665"><h3>Lycopene and Other Components</h3><p id="CDR0000719335__666">One study randomly assigned 79 men before <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045851/" class="def">prostatectomy</a> to a <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044698/" class="def">nutritional</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000454757/" class="def">intervention</a> with tomato products containing 30 mg of lycopene daily; tomato products plus selenium, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045809/" class="def">omega-3 fatty acids</a>, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000407766/" class="def">soy</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046660/" class="def">isoflavones</a>, grape/pomegranate juice, and green/black tea; or a control diet for 3 weeks.[<a class="bk_pop" href="#CDR0000719335_rl_485_3">3</a>] There were no differences in PSA values between the intervention and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044149/" class="def">control groups</a>. However, a post-hoc exploratory analysis found lower PSA values in men with intermediate-risk prostate cancer who consumed the tomato products and in men with the highest increases in lycopene levels.</p></div><div id="CDR0000719335__488"><h3>Zyflamend</h3><div id="CDR0000719335__489"><h4>Overview</h4><ul id="CDR0000719335__490"><li class="half_rhythm"><div>Zyflamend is a dietary supplement that contains both supercritical <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044669/" class="def">fluid</a> (CO<sub>2</sub>) and hydroalcoholic extracts of the following herbs suspended in olive oil: rosemary, turmeric, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000340930/" class="def">ginger</a>, holy basil, green tea, hu zhang, Chinese goldthread, barberry, oregano, and Baikal skullcap.</div></li><li class="half_rhythm"><div>The individual components of Zyflamend have <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044187/" class="def">anti-inflammatory</a> and possible <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044272/" class="def">anticarcinogenic</a> properties.</div></li><li class="half_rhythm"><div>In various <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044517/" class="def">preclinical studies</a>, Zyflamend has been shown to suppress the expression of certain <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000045693/" class="def">genes</a> involved in the <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000373080/" class="def">inflammatory</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044085/" class="def">response</a> and in <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045333/" class="def">cancer</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044078/" class="def">progression</a>, such as cyclooxygenase 1(COX-1), <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000589403/" class="def">COX-2</a>, 5-lipoxygenase (5-LOX), and 12-LOX.</div></li><li class="half_rhythm"><div>In other preclinical studies, Zyflamend demonstrated single-agent anticancer activity, and it improved cancer suppression when used with hormonal and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045214/" class="def">chemotherapy</a> agents.</div></li><li class="half_rhythm"><div>Results of a <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045830/" class="def">phase I</a> study of Zyflamend suggest that use of this supplement is not associated with serious <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000445093/" class="def">toxicity</a> or <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044922/" class="def">adverse effects</a>.</div></li></ul></div><div id="CDR0000719335__491"><h4>General information and history</h4><p id="CDR0000719335__492">Zyflamend is a dietary supplement that contains both supercritical fluid (CO<sub>2</sub>) and hydroalcoholic extracts of the following herbs suspended in olive oil:</p><ul id="CDR0000719335__592"><li class="half_rhythm"><div> Rosemary (<i>Rosmarinus officinalis</i> L.).</div></li><li class="half_rhythm"><div>Turmeric (<i>Curcuma longa</i> L.).</div></li><li class="half_rhythm"><div>Ginger (<i>Zingiber officinale</i> Roscoe).</div></li><li class="half_rhythm"><div>Holy basil (<i>Ocimum sanctum</i> L.).</div></li><li class="half_rhythm"><div>Green tea (<i>Camellia sinensis</i> [L.] Kuntze).</div></li><li class="half_rhythm"><div>Hu zhang (<i>Polygonum cuspidatum</i> Siebold & Zucc.).</div></li><li class="half_rhythm"><div>Chinese goldthread (<i>Coptis chinensis</i> Franch.).</div></li><li class="half_rhythm"><div>Barberry (<i>Berberis vulgaris</i> L.).</div></li><li class="half_rhythm"><div>Oregano (<i>Origanum vulgare</i> L.).</div></li><li class="half_rhythm"><div>Baikal skullcap (<i>Scutellaria baicalensis</i> Georgi).</div></li></ul><p id="CDR0000719335__594">The individual components of Zyflamend have anti-inflammatory and possible anticarcinogenic properties. For example, results of a 2011 study suggest that Zyflamend may inhibit the growth of <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045135/" class="def">melanoma</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046476/" class="def">cells</a>.[<a class="bk_pop" href="#CDR0000719335_rl_485_4">4</a>]</p><p id="CDR0000719335__493">The extracts in Zyflamend have been shown to have anti-inflammatory effects via inhibition of cyclooxygenase (COX) activity. COXs are <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046081/" class="def">enzymes</a> that convert arachidonic <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000642987/" class="def">acid</a> into <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000559143/" class="def">prostaglandins</a>, which are thought to play a role in <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046634/" class="def">tumor</a> development and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046710/" class="def">metastasis</a>. One COX enzyme, COX-2, is activated during <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045641/" class="def">chronic</a> disease states, such as cancer.[<a class="bk_pop" href="#CDR0000719335_rl_485_5">5</a>]</p><p id="CDR0000719335__494">The antitumorigenic mechanisms of action of Zyflamend are unknown, but according to one study, Zyflamend may suppress activation of nuclear factor-kappa B (NF-kappa B) (a nuclear <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000390290/" class="def">transcription</a> factor involved in tumorigenesis) and NF-kappa B–regulated gene products.[<a class="bk_pop" href="#CDR0000719335_rl_485_6">6</a>]</p></div><div id="CDR0000719335__495"><h4>Preclinical/animal studies</h4><div id="CDR0000719335__496"><h5><i>In vitro</i> studies</h5><p id="CDR0000719335__497">In a study reported in 2012, human <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000445079/" class="def">prostate cancer</a> cells were treated <i><a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045733/" class="def">in vitro</a></i> with Zyflamend. Cells treated with the supplement at concentrations ranging from 0.06 to 0.5 <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000655121/" class="def">μL</a>/<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000655103/" class="def">mL</a> exhibited <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044110/" class="def">dose-dependent</a> decreases in <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045592/" class="def">androgen</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044958/" class="def">receptor</a> and PSA expression levels compared with cells treated with the <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044097/" class="def">dimethyl sulfoxide</a> vehicle control. Prostate cancer cells that were treated with a combination of Zyflamend (0.06 μL/mL) and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045354/" class="def">bicalutamide</a> (25 <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000659790/" class="def">μM</a>), an androgen receptor inhibitor, showed reductions in cell growth, PSA expression, and antiapoptotic <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000557359/" class="def">protein expression</a> compared with cells treated with Zyflamend or bicalutamide alone.[<a class="bk_pop" href="#CDR0000719335_rl_485_7">7</a>]</p><p id="CDR0000719335__498">Although the individual components of Zyflamend have been shown to influence COX activity, one study examined the effects of the <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000348921/" class="def">drug</a> on COX-1 and COX-2 expression in prostate cancer cells. The results revealed that Zyflamend, at a <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000683342/" class="def">concentration</a> of 0.9 μL/mL, inhibited expression of both COX-1 and COX-2. At a concentration of 0.45 μL/mL, the degree of COX-2 inhibition was observed, but the level of COX-1 inhibition was reduced by 50%. At a concentration of 0.1 μL/mL, Zyflamend effectively inhibited growth of prostate cancer cells and increased the level of caspase-3, a proapoptotic enzyme. However, a separate experiment indicated that the prostate cancer cells used in the study (LNCaP cells, which are androgen sensitive) did not express high levels of COX-2, suggesting that Zyflamend’s effects on prostate cancer cells may result from a COX-independent mechanism.[<a class="bk_pop" href="#CDR0000719335_rl_485_5">5</a>]</p><p id="CDR0000719335__499">The lipoxygenase isozymes 5-LOX and 12-LOX are also proteins associated with <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044042/" class="def">inflammation</a> and tumor growth. In a 2007 study, the effects of Zyflamend on 5-LOX and 12-LOX expression were investigated. The findings indicated that 0.25 μL/mL to 2 μL/mL of Zyflamend produced decreases in 5-LOX and 12-LOX expression in PC3 prostate cancer cells (cells that have high <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044058/" class="def">metastatic</a> potential). The supplement also inhibited <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046479/" class="def">cell proliferation</a> and induced <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046524/" class="def">apoptosis</a>. In addition, Zyflamend treatment resulted in a decrease in Rb <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000641137/" class="def">phosphorylation</a> (Rb proteins control <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000597111/" class="def">cell-cycle</a>-related genes). These results indicate that Zyflamend may inhibit prostate cancer cell growth through a variety of mechanisms.[<a class="bk_pop" href="#CDR0000719335_rl_485_8">8</a>]</p><p id="CDR0000719335__500">In a 2011 study, human prostate cancer cells were treated with Zyflamend (200 <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000306521/" class="def">µg</a>/mL). After 48 hours of treatment, a <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044167/" class="def">statistically significant</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000654999/" class="def">reduction</a> in cell growth was observed for Zyflamend-treated cells, compared with control cells (<i>P</i> < .005). In another experiment, prostate cancer cells were treated with <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000653119/" class="def">insulin-like growth factor</a>-1 (IGF-1; 0–100 <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000285977/" class="def">ng</a>/mL) alone or in combination with Zyflamend (200 µg/mL). Cells treated with IGF-1 alone exhibited statistically significant, dose-dependent increases in cell proliferation, whereas cells treated with both IGF-1 and Zyflamend showed significant decreases in cell proliferation. Zyflamend was also shown to decrease cellular levels of the IGF-1 receptor and the androgen receptor in prostate cancer cells.[<a class="bk_pop" href="#CDR0000719335_rl_485_9">9</a>] A 2014 investigation by this team found that Zyflamend inhibits the expression of class I and class II histone deacetylases (HDAC) and upregulated their downstream target p21 suppressor gene.[<a class="bk_pop" href="#CDR0000719335_rl_485_10">10</a>] The extracts of the individual components of the 10 botanicals in Zyflamend were also evaluated in an effort to identify which compounds contributed most to the inhibition of HDAC expression. Chinese goldthread and baikal skullcap appeared to be the most likely major contributors to the overall Zyflamend effect on HDAC expression.</p></div><div id="CDR0000719335__501"><h5>Animal studies</h5><p id="CDR0000719335__502">Additional evidence that Zyflamend promotes apoptosis in cancer cells was obtained in laboratory and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000454774/" class="def">animal studies</a> reported in 2012.[<a class="bk_pop" href="#CDR0000719335_rl_485_11">11</a>] Treatment of human <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046685/" class="def">colorectal</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045963/" class="def">carcinoma</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044016/" class="def">cell lines</a>
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<i>in vitro</i> with Zyflamend was shown to significantly down regulate expression of antiapoptotic proteins, up regulate expression of Bax (a proapoptotic <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046092/" class="def">protein</a>), and increase expression of <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000641151/" class="def">death receptor 5</a> (DR5), a receptor important in apoptosis. Moreover, when nude mice with <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044521/" class="def">pancreatic cancer</a> cell implants were randomly assigned to receive Zyflamend or a control treatment for 4 weeks, tumor cells from the Zyflamend-treated mice showed significant reductions in antiapoptotic proteins and significantly increased expression of DR5, compared with tumor cells from control-treated animals.</p><p id="CDR0000719335__503">In a 2011 study, mice were also implanted with pancreatic cancer cells and then treated with <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045347/" class="def">gemcitabine</a> and/or Zyflamend. The combination treatment resulted in a significantly greater decrease in tumor growth than did treatment with gemcitabine or Zyflamend alone. Other findings from this study suggest that Zyflamend exerted its effects by sensitizing the pancreatic tumors to gemcitabine through suppression of multiple targets linked to tumorigenesis.[<a class="bk_pop" href="#CDR0000719335_rl_485_12">12</a>]</p></div></div><div id="CDR0000719335__504"><h4>Human studies</h4><div id="CDR0000719335__505"><h5>Intervention studies</h5><p id="CDR0000719335__506">In one <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044007/" class="def">case report</a>, a patient with HGPIN received Zyflamend 3 times daily for 18 months. Zyflamend did not affect this patient's PSA level, but, after 18 months, repeat core <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045164/" class="def">biopsies</a> of the prostate did not show PIN or cancer.[<a class="bk_pop" href="#CDR0000719335_rl_485_13">13</a>]</p><p id="CDR0000719335__507">In a 2009 phase I study designed to assess safety and toxicity, patients with HGPIN were assigned to take Zyflamend (780 <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044213/" class="def">mg</a>) 3 times daily for 18 months, plus combinations of dietary supplements (i.e., <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000658861/" class="def">probiotic</a> supplement, multivitamin, green and white tea extract, Baikal skullcap, docosahexaenoic acid, holy basil, and turmeric). Zyflamend and the additional dietary supplements were well tolerated by the patients, and no serious adverse events occurred. After 18 months of treatment, 60% of the study subjects had only <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045614/" class="def">benign</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046683/" class="def">tissue</a> at biopsy; 26.7% had HGPIN in one core; and 13.3% had prostate cancer.[<a class="bk_pop" href="#CDR0000719335_rl_485_14">14</a>]</p></div></div><div id="CDR0000719335__508"><h4>Adverse effects</h4><p id="CDR0000719335__509">Zyflamend was well tolerated in the previously described 2009 <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044195/" class="def">clinical study</a>. Mild heartburn was reported in 9 of 23 subjects, but it resolved when the study supplements were taken with food. No serious toxicity or adverse events were reported in the study.[<a class="bk_pop" href="#CDR0000719335_rl_485_14">14</a>]</p></div></div><div id="CDR0000719335_rl_485"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000719335_rl_485_1">Thomas R, Williams M, Sharma H, et al.: A double-blind, placebo-controlled randomised trial evaluating the effect of a polyphenol-rich whole food supplement on PSA progression in men with prostate cancer--the U.K. NCRN Pomi-T study. Prostate Cancer Prostatic Dis 17 (2): 180-6, 2014. [<a href="/pmc/articles/PMC4020278/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4020278</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/24614693" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24614693</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_485_2">Gontero P, Marra G, Soria F, et al.: A randomized double-blind placebo controlled phase I-II study on clinical and molecular effects of dietary supplements in men with precancerous prostatic lesions. Chemoprevention or "chemopromotion"? Prostate 75 (11): 1177-86, 2015. [<a href="https://pubmed.ncbi.nlm.nih.gov/25893930" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25893930</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_485_3">Paur I, Lilleby W, Bøhn SK, et al.: Tomato-based randomized controlled trial in prostate cancer patients: Effect on PSA. Clin Nutr 36 (3): 672-679, 2017. [<a href="https://pubmed.ncbi.nlm.nih.gov/27406859" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 27406859</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_485_4">Ekmekcioglu S, Chattopadhyay C, Akar U, et al.: Zyflamend mediates therapeutic induction of autophagy to apoptosis in melanoma cells. Nutr Cancer 63 (6): 940-9, 2011. [<a href="https://pubmed.ncbi.nlm.nih.gov/21745040" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21745040</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_485_5">Bemis DL, Capodice JL, Anastasiadis AG, et al.: Zyflamend, a unique herbal preparation with nonselective COX inhibitory activity, induces apoptosis of prostate cancer cells that lack COX-2 expression. Nutr Cancer 52 (2): 202-12, 2005. [<a href="https://pubmed.ncbi.nlm.nih.gov/16201851" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16201851</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_485_6">Sandur SK, Ahn KS, Ichikawa H, et al.: Zyflamend, a polyherbal preparation, inhibits invasion, suppresses osteoclastogenesis, and potentiates apoptosis through down-regulation of NF-kappa B activation and NF-kappa B-regulated gene products. Nutr Cancer 57 (1): 78-87, 2007. [<a href="https://pubmed.ncbi.nlm.nih.gov/17516865" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17516865</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_485_7">Yan J, Xie B, Capodice JL, et al.: Zyflamend inhibits the expression and function of androgen receptor and acts synergistically with bicalutimide to inhibit prostate cancer cell growth. Prostate 72 (3): 244-52, 2012. [<a href="https://pubmed.ncbi.nlm.nih.gov/21656835" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21656835</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_485_8">Yang P, Cartwright C, Chan D, et al.: Zyflamend-mediated inhibition of human prostate cancer PC3 cell proliferation: effects on 12-LOX and Rb protein phosphorylation. Cancer Biol Ther 6 (2): 228-36, 2007. [<a href="https://pubmed.ncbi.nlm.nih.gov/17218785" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17218785</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_485_9">Huang EC, Chen G, Baek SJ, et al.: Zyflamend reduces the expression of androgen receptor in a model of castrate-resistant prostate cancer. Nutr Cancer 63 (8): 1287-96, 2011. [<a href="https://pubmed.ncbi.nlm.nih.gov/21958043" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21958043</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_485_10">Huang EC, Zhao Y, Chen G, et al.: Zyflamend, a polyherbal mixture, down regulates class I and class II histone deacetylases and increases p21 levels in castrate-resistant prostate cancer cells. BMC Complement Altern Med 14: 68, 2014. [<a href="/pmc/articles/PMC3938081/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3938081</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/24555771" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24555771</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_485_11">Kim JH, Park B, Gupta SC, et al.: Zyflamend sensitizes tumor cells to TRAIL-induced apoptosis through up-regulation of death receptors and down-regulation of survival proteins: role of ROS-dependent CCAAT/enhancer-binding protein-homologous protein pathway. Antioxid Redox Signal 16 (5): 413-27, 2012. [<a href="/pmc/articles/PMC3261028/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3261028</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/22004570" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22004570</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_485_12">Kunnumakkara AB, Sung B, Ravindran J, et al.: Zyflamend suppresses growth and sensitizes human pancreatic tumors to gemcitabine in an orthotopic mouse model through modulation of multiple targets. Int J Cancer 131 (3): E292-303, 2012. [<a href="/pmc/articles/PMC3288649/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3288649</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/21935918" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21935918</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_485_13">Rafailov S, Cammack S, Stone BA, et al.: The role of Zyflamend, an herbal anti-inflammatory, as a potential chemopreventive agent against prostate cancer: a case report. Integr Cancer Ther 6 (1): 74-6, 2007. [<a href="https://pubmed.ncbi.nlm.nih.gov/17351029" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17351029</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_485_14">Capodice JL, Gorroochurn P, Cammack AS, et al.: Zyflamend in men with high-grade prostatic intraepithelial neoplasia: results of a phase I clinical trial. J Soc Integr Oncol 7 (2): 43-51, 2009. [<a href="https://pubmed.ncbi.nlm.nih.gov/19476738" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19476738</span></a>]</div></li></ol></div></div><div id="CDR0000719335__387"><h2 id="_CDR0000719335__387_">Other Prostate Health Supplements</h2><div id="CDR0000719335__388"><h3>Overview</h3><p id="CDR0000719335__389">Many widely available <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000373932/" class="def">dietary supplements</a> are marketed to support <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046539/" class="def">prostate</a> health. African cherry (<i>Pygeum africanum</i>) and beta-sitosterol are two related supplements that have been studied as potential <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000445079/" class="def">prostate cancer</a> treatments. Note: A separate <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044271/" class="def">PDQ</a> summary on <a href="/books/n/pdqcis/CDR0000404384/">PC-SPES</a> is also available.</p></div><div id="CDR0000719335__390"><h3>African Cherry/<i>P. africanum</i></h3><p id="CDR0000719335__391"><i>P. africanum</i> is a tree from the Rosaceae family that grows in tropical zones. It is found in a number of African countries including Kenya, Madagascar, Uganda, and Nigeria. Bark from the <i>P. africanum</i> tree was used by African tribes to treat <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044093/" class="def">urinary</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045022/" class="def">symptoms</a> and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046770/" class="def">gastric</a> pain.[<a class="bk_pop" href="#CDR0000719335_rl_387_1">1</a>] In the 18th century, European travelers learned from South African tribes that <i>P. africanum</i> was used to treat <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046501/" class="def">bladder</a> discomfort and “old man’s disease” (enlarged prostate). </p><p id="CDR0000719335__392">Since 1969, bark <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000407760/" class="def">extracts</a> from <i>P. africanum</i> have been available as <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044711/" class="def">prescription</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000348921/" class="def">drugs</a> in Europe and have been widely used to treat <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046509/" class="def">benign prostatic hyperplasia</a>.[<a class="bk_pop" href="#CDR0000719335_rl_387_2">2</a>,<a class="bk_pop" href="#CDR0000719335_rl_387_3">3</a>] The bark contains a number of <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000422394/" class="def">compounds</a> including <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000463732/" class="def">saturated</a> and unsaturated <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045689/" class="def">fatty acids</a>, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044485/" class="def">phytosterols</a> (e.g., beta-sitosterol), pentacyclic triterpenoids (e.g., oleanolic acid), alcohols, and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000285960/" class="def">carbohydrates</a>. The extract is obtained by macerating and solubilizing the bark in an organic <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000463162/" class="def">solvent</a>. The extract is then purified from the solvent.[<a class="bk_pop" href="#CDR0000719335_rl_387_1">1</a>]</p><p id="CDR0000719335__393">Two components of <i>P. africanum</i> bark extracts, atraric acid and N-butylbenzene-<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000367474/" class="def">sulfonamide</a>, are <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045592/" class="def">androgen</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044958/" class="def">receptor</a> inhibitors, as indicated by both <i><a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045733/" class="def">in vitro</a></i> [<a class="bk_pop" href="#CDR0000719335_rl_387_4">4</a>-<a class="bk_pop" href="#CDR0000719335_rl_387_6">6</a>] and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000454774/" class="def">animal</a>
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<i><a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046352/" class="def">in vivo</a></i> [<a class="bk_pop" href="#CDR0000719335_rl_387_7">7</a>] studies. This activity is produced by each of these components at <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000683342/" class="def">concentrations</a> that are significantly lower than the clinically achieved concentration of the <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046052/" class="def">antiandrogen</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045264/" class="def">flutamide</a>.[<a class="bk_pop" href="#CDR0000719335_rl_387_8">8</a>]</p></div><div id="CDR0000719335__394"><h3>Beta-Sitosterol</h3><p id="CDR0000719335__395">Beta-sitosterol is a member of the phytosterol family of <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044709/" class="def">phytochemicals</a>. It is found ubiquitously in plants. <i> Pygeum africanum</i>, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000514413/" class="def">saw palmetto</a> (<i>Serenoa repens</i>), and some legumes can contain rather high concentrations. As a type of phytosterol (or <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044161/" class="def">plant sterol</a>), beta-sitosterol has a similar structure to <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000407756/" class="def">cholesterol</a>. Phytosterols, including beta-sitosterol, reduce <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000463702/" class="def">absorption</a> of dietary cholesterol and their potential to protect against <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000748137/" class="def">cardiovascular disease</a> is under investigation. <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000285973/" class="def">Mean</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045839/" class="def">plasma</a> beta-sitosterol concentration in a small group of healthy male volunteers in Vienna, Austria, was 2.83 <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000306521/" class="def">μg</a>/<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044214/" class="def">mL</a> (approximately 7 <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000372932/" class="def">μM</a>).[<a class="bk_pop" href="#CDR0000719335_rl_387_9">9</a>] Interestingly, however, a rare <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000651193/" class="def">condition</a> caused by <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000046063/" class="def">mutations</a> in the <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045009/" class="def">adenosine triphosphate</a>-binding cassette (ABC) transporter <i>ABCG5</i> or <i>ABCG8</i>
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<a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000045693/" class="def">genes</a> results in an <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045098/" class="def">inherited</a> sterol storage disease with markedly increased <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044088/" class="def">serum</a> concentrations of plant sterols such as sitosterol and leads to premature atherosclerosis and large xanthomas.[<a class="bk_pop" href="#CDR0000719335_rl_387_10">10</a>]</p><p id="CDR0000719335__396">Research has also suggested that phytosterols may have <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044272/" class="def">anticarcinogenic</a> properties, but the exact mechanisms are unknown.[<a class="bk_pop" href="#CDR0000719335_rl_387_11">11</a>] Phytosterols may exert <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000446109/" class="def">antitumor</a> effects by acting on immune and hormonal systems, or by directly targeting <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000597111/" class="def">cell cycles</a> and inducing <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046524/" class="def">apoptosis</a> in <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046634/" class="def">tumor</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046476/" class="def">cells</a>.[<a class="bk_pop" href="#CDR0000719335_rl_387_12">12</a>]</p><p id="CDR0000719335__397">Beta-sitosterol at very high concentrations (i.e., 16 <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000659791/" class="def">mM</a> or 6.64 <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044213/" class="def">mg</a>/mL) has been shown to significantly inhibit growth of PC-3 prostate cancer cells and induce apoptosis.[<a class="bk_pop" href="#CDR0000719335_rl_387_13">13</a>,<a class="bk_pop" href="#CDR0000719335_rl_387_14">14</a>] Beta-sitosterol is very poorly <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044225/" class="def">bioavailable</a>, with an estimated 0.41% of dietary beta-sitosterol absorbed, and circulating <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000270735/" class="def">blood</a> levels of about 3 μg/mL to 9 μg/mL in individuals consuming diets containing normal to high amounts of plant-based foods (approximately 1,000 times less than the concentration used in the study).[<a class="bk_pop" href="#CDR0000719335_rl_387_9">9</a>,<a class="bk_pop" href="#CDR0000719335_rl_387_15">15</a>] Associated with these effects are decreasing levels of cell cycle regulators p21 and p27 in the cancer cells and an increased production of <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000687227/" class="def">reactive oxygen species</a>. </p></div><div id="CDR0000719335_rl_387"><h3>References</h3><ol><li><div class="bk_ref" id="CDR0000719335_rl_387_1">Brackman FG, Edgar A, Coates PM: Pygeum. In: Coates PM, Betz JM, Blackman MR, et al., eds.: Encyclopedia of Dietary Supplements. 2nd ed. New York, NY: Informa Healthcare, 2010, pp 650-5.</div></li><li><div class="bk_ref" id="CDR0000719335_rl_387_2">Ishani A, MacDonald R, Nelson D, et al.: Pygeum africanum for the treatment of patients with benign prostatic hyperplasia: a systematic review and quantitative meta-analysis. Am J Med 109 (8): 654-64, 2000. [<a href="https://pubmed.ncbi.nlm.nih.gov/11099686" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11099686</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_387_3">Levin RM, Das AK: A scientific basis for the therapeutic effects of Pygeum africanum and Serenoa repens. Urol Res 28 (3): 201-9, 2000. [<a href="https://pubmed.ncbi.nlm.nih.gov/10929430" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10929430</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_387_4">Papaioannou M, Schleich S, Prade I, et al.: The natural compound atraric acid is an antagonist of the human androgen receptor inhibiting cellular invasiveness and prostate cancer cell growth. J Cell Mol Med 13 (8B): 2210-23, 2009. [<a href="/pmc/articles/PMC6512379/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC6512379</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/18627423" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18627423</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_387_5">Papaioannou M, Schleich S, Roell D, et al.: NBBS isolated from Pygeum africanum bark exhibits androgen antagonistic activity, inhibits AR nuclear translocation and prostate cancer cell growth. Invest New Drugs 28 (6): 729-43, 2010. [<a href="https://pubmed.ncbi.nlm.nih.gov/19771394" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19771394</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_387_6">Schleich S, Papaioannou M, Baniahmad A, et al.: Extracts from Pygeum africanum and other ethnobotanical species with antiandrogenic activity. Planta Med 72 (9): 807-13, 2006. [<a href="https://pubmed.ncbi.nlm.nih.gov/16783690" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16783690</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_387_7">Shenouda NS, Sakla MS, Newton LG, et al.: Phytosterol Pygeum africanum regulates prostate cancer in vitro and in vivo. Endocrine 31 (1): 72-81, 2007. [<a href="https://pubmed.ncbi.nlm.nih.gov/17709901" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17709901</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_387_8">Handratta VD, Vasaitis TS, Njar VC, et al.: Novel C-17-heteroaryl steroidal CYP17 inhibitors/antiandrogens: synthesis, in vitro biological activity, pharmacokinetics, and antitumor activity in the LAPC4 human prostate cancer xenograft model. J Med Chem 48 (8): 2972-84, 2005. [<a href="https://pubmed.ncbi.nlm.nih.gov/15828836" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15828836</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_387_9">Duchateau G, Cochrane B, Windebank S, et al.: Absolute oral bioavailability and metabolic turnover of β-sitosterol in healthy subjects. Drug Metab Dispos 40 (10): 2026-30, 2012. [<a href="https://pubmed.ncbi.nlm.nih.gov/22826463" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22826463</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_387_10">Tsubakio-Yamamoto K, Nishida M, Nakagawa-Toyama Y, et al.: Current therapy for patients with sitosterolemia--effect of ezetimibe on plant sterol metabolism. J Atheroscler Thromb 17 (9): 891-900, 2010. [<a href="https://pubmed.ncbi.nlm.nih.gov/20543520" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20543520</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_387_11">Awad AB, Fink CS: Phytosterols as anticancer dietary components: evidence and mechanism of action. J Nutr 130 (9): 2127-30, 2000. [<a href="https://pubmed.ncbi.nlm.nih.gov/10958802" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10958802</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_387_12">Bradford PG, Awad AB: Phytosterols as anticancer compounds. Mol Nutr Food Res 51 (2): 161-70, 2007. [<a href="https://pubmed.ncbi.nlm.nih.gov/17266177" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17266177</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_387_13">Awad AB, Burr AT, Fink CS: Effect of resveratrol and beta-sitosterol in combination on reactive oxygen species and prostaglandin release by PC-3 cells. Prostaglandins Leukot Essent Fatty Acids 72 (3): 219-26, 2005. [<a href="https://pubmed.ncbi.nlm.nih.gov/15664307" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15664307</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_387_14">Scholtysek C, Krukiewicz AA, Alonso JL, et al.: Characterizing components of the Saw Palmetto Berry Extract (SPBE) on prostate cancer cell growth and traction. Biochem Biophys Res Commun 379 (3): 795-8, 2009. [<a href="https://pubmed.ncbi.nlm.nih.gov/19059205" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19059205</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_387_15">Muti P, Awad AB, Schünemann H, et al.: A plant food-based diet modifies the serum beta-sitosterol concentration in hyperandrogenic postmenopausal women. J Nutr 133 (12): 4252-5, 2003. [<a href="https://pubmed.ncbi.nlm.nih.gov/14652381" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 14652381</span></a>]</div></li></ol></div></div><div id="CDR0000719335__56"><h2 id="_CDR0000719335__56_">Changes to This Summary (08/10/2017)</h2><p id="CDR0000719335__57">The PDQ cancer information summaries are reviewed regularly and updated as
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new information becomes available. This section describes the latest
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changes made to this summary as of the date above.</p><p id="CDR0000719335__678">Editorial changes were made to this summary.</p><p id="CDR0000719335__disclaimerHP_3">This summary is written and maintained by the <a href="http://www.cancer.gov/publications/pdq/editorial-boards/cam" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PDQ Integrative, Alternative, and Complementary Therapies Editorial Board</a>, which is
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editorially independent of NCI. The summary reflects an independent review of
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the literature and does not represent a policy statement of NCI or NIH. More
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information about summary policies and the role of the PDQ Editorial Boards in
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maintaining the PDQ summaries can be found on the <a href="#CDR0000719335__AboutThis_1">About This PDQ Summary</a> and <a href="http://www.cancer.gov/publications/pdq" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PDQ® - NCI's Comprehensive Cancer Database</a> pages.
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</p></div><div id="CDR0000719335__AboutThis_1"><h2 id="_CDR0000719335__AboutThis_1_">About This PDQ Summary</h2><div id="CDR0000719335__AboutThis_2"><h3>Purpose of This Summary</h3><p id="CDR0000719335__AboutThis_3">This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the use of nutrition and dietary supplements for reducing the risk of developing prostate cancer or for treating prostate cancer. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.</p></div><div id="CDR0000719335__AboutThis_4"><h3>Reviewers and Updates</h3><p id="CDR0000719335__AboutThis_5">This summary is reviewed regularly and updated as necessary by the <a href="http://www.cancer.gov/publications/pdq/editorial-boards/cam" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PDQ Integrative, Alternative, and Complementary Therapies Editorial Board</a>, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).</p><p id="CDR0000719335__AboutThis_22"> Board members review recently published articles each month to determine whether an article should:</p><ul id="CDR0000719335__AboutThis_6"><li class="half_rhythm"><div>be discussed at a meeting,</div></li><li class="half_rhythm"><div>be cited with text, or</div></li><li class="half_rhythm"><div>replace or update an existing article that is already cited.</div></li></ul><p id="CDR0000719335__AboutThis_7">Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.</p><p>The lead reviewers for Prostate Cancer, Nutrition, and Dietary Supplements are:</p><ul><li class="half_rhythm"><div>Donald I. Abrams, MD (UCSF Osher Center for Integrative Medicine)</div></li><li class="half_rhythm"><div>Nagi B. Kumar, PhD, RD, FADA (Fellow of the American Dietetic Association)</div></li><li class="half_rhythm"><div>Channing J Paller, MD (Johns Hopkins Hospital)</div></li><li class="half_rhythm"><div>Jeffrey D. White, MD (National Cancer Institute)</div></li></ul><p id="CDR0000719335__AboutThis_9">Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's <a href="https://www.cancer.gov/contact/email-us" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Email Us</a>. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.</p></div><div id="CDR0000719335__AboutThis_10"><h3>Levels of Evidence</h3><p id="CDR0000719335__AboutThis_11">Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Integrative, Alternative, and Complementary Therapies Editorial Board uses a <a href="/books/n/pdqcis/CDR0000256874/">formal evidence ranking system</a> in developing its level-of-evidence designations.</p></div><div id="CDR0000719335__AboutThis_12"><h3>Permission to Use This Summary</h3><p id="CDR0000719335__AboutThis_13">PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”</p><p id="CDR0000719335__AboutThis_14">The preferred citation for this PDQ summary is:</p><p id="CDR0000719335__AboutThis_15">PDQ® Integrative, Alternative, and Complementary Therapies Editorial Board. PDQ Prostate Cancer, Nutrition, and Dietary Supplements. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: <a href="https://www.cancer.gov/about-cancer/treatment/cam/hp/prostate-supplements-pdq" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">https://www.cancer.gov/about-cancer/treatment/cam/hp/prostate-supplements-pdq</a>. Accessed <MM/DD/YYYY>. [PMID: 26389500]</p><p id="CDR0000719335__AboutThis_16">Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in <a href="https://visualsonline.cancer.gov/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Visuals Online</a>, a collection of over 2,000 scientific images.
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</p></div><div id="CDR0000719335__AboutThis_17"><h3>Disclaimer</h3><p id="CDR0000719335__AboutThis_19">The information in these summaries should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the <a href="https://www.cancer.gov/about-cancer/managing-care" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Managing Cancer Care</a> page.</p></div><div id="CDR0000719335__AboutThis_20"><h3>Contact Us</h3><p id="CDR0000719335__AboutThis_21">More information about contacting us or receiving help with the Cancer.gov website can be found on our <a href="https://www.cancer.gov/contact" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Contact Us for Help</a> page. Questions can also be submitted to Cancer.gov through the website’s <a href="https://www.cancer.gov/contact/email-us" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Email Us</a>.</p></div></div></div></div>
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2019</li><li><span class="bk_col_itm"><a href="/books/NBK83261.22/">NBK83261.22</a></span> September 24, 2019</li><li><span class="bk_col_itm"><a href="/books/NBK83261.21/">NBK83261.21</a></span> June 5, 2019</li><li><span class="bk_col_itm"><a href="/books/NBK83261.20/">NBK83261.20</a></span> January 14, 2019</li><li><span class="bk_col_itm"><a href="/books/NBK83261.19/">NBK83261.19</a></span> January 10, 2019</li><li><span class="bk_col_itm"><a href="/books/NBK83261.18/">NBK83261.18</a></span> August 16, 2018</li><li><span class="bk_col_itm"><a href="/books/NBK83261.17/">NBK83261.17</a></span> May 10, 2018</li><li><span class="bk_col_itm"><a href="/books/NBK83261.16/">NBK83261.16</a></span> February 1, 2018</li><li><span class="bk_col_itm"><a href="/books/NBK83261.15/">NBK83261.15</a></span> October 20, 2017</li><li><span class="bk_col_itm"><a href="/books/NBK83261.14/">NBK83261.14</a></span> September 13, 2017</li><li><span class="bk_col_itm">NBK83261.13</span> August 10, 2017 (Displayed Version)</li><li><span class="bk_col_itm"><a href="/books/NBK83261.12/">NBK83261.12</a></span> June 6, 2017</li><li><span class="bk_col_itm"><a href="/books/NBK83261.11/">NBK83261.11</a></span> April 7, 2017</li><li><span class="bk_col_itm"><a href="/books/NBK83261.10/">NBK83261.10</a></span> January 19, 2017</li><li><span class="bk_col_itm"><a href="/books/NBK83261.9/">NBK83261.9</a></span> January 6, 2017</li><li><span class="bk_col_itm"><a href="/books/NBK83261.8/">NBK83261.8</a></span> October 21, 2016</li><li><span class="bk_col_itm"><a href="/books/NBK83261.7/">NBK83261.7</a></span> June 10, 2016</li><li><span class="bk_col_itm"><a href="/books/NBK83261.6/">NBK83261.6</a></span> April 19, 2016</li><li><span class="bk_col_itm"><a href="/books/NBK83261.5/">NBK83261.5</a></span> October 21, 2015</li><li><span class="bk_col_itm"><a href="/books/NBK83261.4/">NBK83261.4</a></span> October 14, 2015</li><li><span class="bk_col_itm"><a href="/books/NBK83261.3/">NBK83261.3</a></span> October 8, 2015</li><li><span class="bk_col_itm"><a href="/books/NBK83261.2/">NBK83261.2</a></span> September 18, 2015</li><li><span class="bk_col_itm"><a href="/books/NBK83261.1/">NBK83261.1</a></span> June 17, 2015</li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>In this Page</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="page-toc" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="#CDR0000719335__47" ref="log$=inpage&link_id=inpage">Introduction</a></li><li><a href="#CDR0000719335__426" ref="log$=inpage&link_id=inpage">Calcium</a></li><li><a href="#CDR0000719335__174" ref="log$=inpage&link_id=inpage">Green Tea</a></li><li><a href="#CDR0000719335__16" ref="log$=inpage&link_id=inpage">Lycopene</a></li><li><a href="#CDR0000719335__161" ref="log$=inpage&link_id=inpage">Modified Citrus Pectin</a></li><li><a href="#CDR0000719335__162" ref="log$=inpage&link_id=inpage">Pomegranate</a></li><li><a href="#CDR0000719335__283" ref="log$=inpage&link_id=inpage">Selenium</a></li><li><a href="#CDR0000719335__163" ref="log$=inpage&link_id=inpage">Soy</a></li><li><a href="#CDR0000719335__357" ref="log$=inpage&link_id=inpage">Vitamin D</a></li><li><a href="#CDR0000719335__328" ref="log$=inpage&link_id=inpage">Vitamin E</a></li><li><a href="#CDR0000719335__485" ref="log$=inpage&link_id=inpage">Multicomponent Therapies</a></li><li><a href="#CDR0000719335__387" ref="log$=inpage&link_id=inpage">Other Prostate Health Supplements</a></li><li><a href="#CDR0000719335__56" ref="log$=inpage&link_id=inpage">Changes to This Summary (08/10/2017)</a></li><li><a href="#CDR0000719335__AboutThis_1" ref="log$=inpage&link_id=inpage">About This PDQ Summary</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Related publications</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="document-links" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="/books/NBK83984/">Patient Version</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Related information</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="discovery_db_links" id="Shutter"></a></div><div class="portlet_content"><ul><li class="brieflinkpopper"><a class="brieflinkpopperctrl" 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xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Prostate Cancer Treatment (PDQ®): Health Professional Version.</a><span class="source">[PDQ Cancer Information Summari...]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Prostate Cancer Treatment (PDQ®): Health Professional Version.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">PDQ Adult Treatment Editorial Board. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">PDQ Cancer Information Summaries. 2002</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/26389227" ref="ordinalpos=1&linkpos=2&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Genetics of Prostate Cancer (PDQ®): Health Professional Version.</a><span class="source">[PDQ Cancer Information Summari...]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Genetics of Prostate Cancer (PDQ®): Health Professional Version.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">PDQ Cancer Genetics Editorial Board. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">PDQ Cancer Information Summaries. 2002</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/26389293" ref="ordinalpos=1&linkpos=3&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Nutrition in Cancer Care (PDQ®): Health Professional Version.</a><span class="source">[PDQ Cancer Information Summari...]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Nutrition in Cancer Care (PDQ®): Health Professional Version.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">PDQ Supportive and Palliative Care Editorial Board. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">PDQ Cancer Information Summaries. 2002</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/26389405" ref="ordinalpos=1&linkpos=4&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Prostate Cancer Prevention (PDQ®): Health Professional Version.</a><span class="source">[PDQ Cancer Information Summari...]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Prostate Cancer Prevention (PDQ®): Health Professional Version.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">PDQ Screening and Prevention Editorial Board. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">PDQ Cancer Information Summaries. 2002</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/26389383" ref="ordinalpos=1&linkpos=5&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Prostate Cancer Screening (PDQ®): Health Professional Version.</a><span class="source">[PDQ Cancer Information Summari...]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Prostate Cancer Screening (PDQ®): Health Professional Version.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">PDQ Screening and Prevention Editorial Board. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">PDQ Cancer Information Summaries. 2002</em></div></div></li></ul><a class="seemore" href="/sites/entrez?db=pubmed&cmd=link&linkname=pubmed_pubmed_reviews&uid=26389500" ref="ordinalpos=1&log$=relatedreviews_seeall&logdbfrom=pubmed">See reviews...</a><a class="seemore" href="/sites/entrez?db=pubmed&cmd=link&linkname=pubmed_pubmed&uid=26389500" ref="ordinalpos=1&log$=relatedarticles_seeall&logdbfrom=pubmed">See all...</a></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Recent Activity</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="recent_activity" id="Shutter"></a></div><div class="portlet_content"><div xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" id="HTDisplay" class=""><div 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