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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: April 19, 2016.</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.</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 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 to use CAM or not? A qualitative study published in 2005 described results from interviews with prostate cancer patients who were CAM users or nonusers. The study identified differences in thinking patterns between the two groups and suggested that no specific theme led patients to CAM, rather a combination of ideas directed them. For example, the perception of CAM being 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 suggest that decision making by prostate cancer patients about CAM treatments depends 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="http://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 <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044271/" class="def">PDQ</a> 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 viewed as 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, 2011. <a href="http://seer.cancer.gov/statfacts/html/prost.html#prevalence" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">Available online</a>. Last accessed February 11, 2016.</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 medicines (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>] 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 up 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_19">19</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_20">20</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_21">21</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_22">22</a>]</p><p id="CDR0000719335__521">In a recent review, the U.S. <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000043981/" class="def">Preventive</a> 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_23">23</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_24">24</a>] Since the time of 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_25">25</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 suggest 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="http://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="http://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="http://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="/books/NBK56070/" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">Also available online</a>. Last accessed April 19, 2016. [<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="/pubmedhealth/PMH0060787/" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">Available online</a>. Last accessed April 19, 2016. [<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">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_20">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_21">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_22">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_23">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_24">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 January 7, 2016.</div></li><li><div class="bk_ref" id="CDR0000719335_rl_426_25">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>Epigallocatechin gallate <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000687277/" class="def">(EGCG)</a>, the most abundant catechin in tea, acts 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 <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_CDR0000046479/" class="def">cell proliferation</a>, suppress production of <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046540/" class="def">prostate-specific antigen (PSA)</a> by prostate cancer <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046476/" class="def">cells</a>, and increase prostate cancer cell death <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 green tea catechin solution or EGCG alone was associated with 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 mortality 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. Case-control and cohort studies, so far, have variously shown beneficial or neutral results with the exception of one study that has shown an increased risk of the development of advanced prostate cancer with consumption of green tea.</div></li><li class="half_rhythm"><div>Results from a small <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044840/" class="def">placebo-controlled</a> study of green tea catechins 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) showed a <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044167/" class="def">statistically significant</a> decrease in the development of prostate cancer among men who were randomly assigned to receive the catechin <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045916/" class="def">supplement</a>. A larger, multicenter, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045858/" class="def">randomized trial</a> is now under way.</div></li><li class="half_rhythm"><div>Studies of orally administered mixtures of tea catechins in men with prostate cancer have begun to provide information about biologic effects in this setting but are too preliminary to draw conclusions about <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044168/" class="def">clinical</a> effectiveness.</div></li><li class="half_rhythm"><div>Green tea has been well tolerated in <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044195/" class="def">clinical studies</a> of prostate cancer patients, with the most common <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046580/" class="def">side effects</a> being 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></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 where 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">The English word “tea” has its origins in China. Ch'a is the Mandarin word for “tea.” In the dialect spoken in the southern Chinese province of Fujian, the word for “tea” was pronounced “tay.” This term was borrowed by European traders who bought tea at the southern Chinese ports, and it evolved into tea (English), thé (French), and Tee (German). “Tea” is also used to describe <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045738/" class="def">infusions</a> of medicinal <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000463714/" class="def">herbs</a>, such as sage and calamint.[<a class="bk_pop" href="#CDR0000719335_rl_174_3">3</a>] 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_4">4</a>] and there is evidence that green tea may protect against various forms of cancer.[<a class="bk_pop" href="#CDR0000719335_rl_174_5">5</a>] Many of the health benefits associated with tea have been attributed to polyphenols.Catechins compose most of the polyphenols found in tea; of these, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000687212/" class="def">epigallocatechin-3-gallate</a> (EGCG) has been the most widely researched.[<a class="bk_pop" href="#CDR0000719335_rl_174_6">6</a>] Tea leaves also contain considerable amounts of oligomeric catechins, commonly known as 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">Laboratory experiments have increased our understanding of the reported associations between green tea and prostate cancer. For example, in one study, 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_7">7</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 to radiation alone.[<a class="bk_pop" href="#CDR0000719335_rl_174_8">8</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 <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000641114/" class="def">kinase</a> (<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_9">9</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_10">10</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 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_11">11</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> antigen (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_12">12</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> (MBD) 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_13">13</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">HDAC</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_14">14</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_15">15</a>,<a class="bk_pop" href="#CDR0000719335_rl_174_16">16</a>] A 1 μM solution of EGCG would contain 0.458 μg of EGCG per mL.</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 green tea catechin-treated water (0.3% green tea catechin 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 green tea catechins showed only prostatic intraepithelial neoplasia (PIN) <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046324/" class="def">lesions</a>, suggesting that green tea catechins may help delay the development of prostate <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046634/" class="def">tumors</a>. Furthermore, the results showed that mice treated with green tea catechins had lower prostate <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046683/" class="def">tissue</a> levels of MCM7 (a protein that is important in <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000597136/" class="def">DNA replication</a> and that is up-regulated during cancer <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044078/" class="def">progression</a>) than mice treated with water, suggesting that green tea may delay prostate cancer progression by inhibiting MCM7 expression.[<a class="bk_pop" href="#CDR0000719335_rl_174_17">17</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> injections 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 <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044088/" class="def">serum</a> PSA levels compared to vehicle treatment. These results provide a rationale for the exploration of EGCG treatment in patients with advanced prostate cancer.[<a class="bk_pop" href="#CDR0000719335_rl_174_7">7</a>]</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/week) 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. These findings suggest that the beneficial effects of green tea may be a result of EGCG’s inhibitory actions on the androgen receptor, and, because androgen receptor signaling is generally intact in <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000686077/" class="def">hormone-refractory</a> and hormone-sensitive prostate cancer, green tea has the potential to be useful in both forms of the disease.[<a class="bk_pop" href="#CDR0000719335_rl_174_18">18</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_19">19</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. These findings suggest that green tea may be most beneficial in men <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046450/" class="def">diagnosed</a> with early PIN lesions, men who are at high risk of developing prostate cancer, or men who are undergoing <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045942/" class="def">watchful waiting</a>.[<a class="bk_pop" href="#CDR0000719335_rl_174_19">19</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_20">20</a>] In a third study, TRAMP and wild-type mice were administered green tea polyphenols in drinking water (0.05% green tea polyphenols in drinking water) starting at 4 weeks or 25 weeks after weaning. Consumption of GTP did not affect prostate pathology, but there were <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045921/" class="def">systemic</a> effects. Young animals who received green tea exhibited lower <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045839/" class="def">plasma</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046068/" class="def">lipid</a> levels, regardless of <a href="/books/n/pdqcis/glossary_gen/def-item/glossary_gen_CDR0000660739/" class="def">genotype</a>, than did older animals who received green tea. These findings suggest that age and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044056/" class="def">metabolic</a> capacity may influence the chemopreventive effects of green tea polyphenols.[<a class="bk_pop" href="#CDR0000719335_rl_174_21">21</a>] Using the TRAMP mice model,[<a class="bk_pop" href="#CDR0000719335_rl_174_22">22</a>] one study demonstrated that oral infusion of GTP extract at a human-achievable dose (equivalent to 6 cups of green tea per day) significantly delayed primary tumor incidence and tumor burden, as assessed sequentially by magnetic resonance imaging, decreased prostate weight (64% of baseline) and genitourinary weight (72%), inhibited serum <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000653119/" class="def">insulin-like growth factor</a>-1 (IGF-I), 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 metastasis to distant organ sites.</p><p id="CDR0000719335__257">Disparate observations in preclinical trials may be attributed to the pharmacokinetic properties of the individual catechin (i.e., EGCG vs. whole green tea polyphenols). Compared with green tea polyphenols, EGCG has relatively low oral bioavailability, possibly because of slow absorption and high metabolic clearance by the <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046312/" class="def">liver</a>.[<a class="bk_pop" href="#CDR0000719335_rl_174_23">23</a>,<a class="bk_pop" href="#CDR0000719335_rl_174_24">24</a>] Other potential confounders may include dosage, method of infusion, duration of intervention, and timing of castration, all of which may influence the markers of progression and the antioxidant property of EGCG. Oral administration of GTP, versus pure EGCG, in drinking water to TRAMP mice may have contributed to higher systemic exposure compared with gavage administration. This may explain the protective effects observed,[<a class="bk_pop" href="#CDR0000719335_rl_174_19">19</a>,<a class="bk_pop" href="#CDR0000719335_rl_174_22">22</a>,<a class="bk_pop" href="#CDR0000719335_rl_174_25">25</a>,<a class="bk_pop" href="#CDR0000719335_rl_174_26">26</a>] compared with studies that failed to demonstrate similar effect.[<a class="bk_pop" href="#CDR0000719335_rl_174_23">23</a>] Overall, these preclinical studies have informed the design and evaluation of GTP in prostate cancer <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000439419/" class="def">prevention</a> and treatment in clinical trials.</p></div><div id="CDR0000719335__258"><h4>Animal safety studies</h4><p id="CDR0000719335__259"> In the National Cancer Institute's (NCI) Division of Cancer Prevention (DCP) 9-month oral toxicity study, Polyphenon E, a botanical drug substance containing a mixture of catechins, was administered (200, 500, or 1,000 mg/kg/day) to fasted male and female beagle dogs. The study was terminated prematurely because of excessive loss of animals due to morbidity and mortality in all treatment groups. Gross necropsy revealed therapy-induced lesions in the gastrointestinal tract, liver, kidneys, reproductive organs, and hematopoietic tissues of treated male and female dogs. An investigation to determine the cause of the toxicity is ongoing; administration of the agent to fasted dogs may have caused increased toxicity in the 9-month versus 13-week NCI DCP-sponsored follow-up study. In the 13-week follow-up study, the no-observed-adverse-effect–level was greater than 600 mg/kg/day of Polyphenon E. 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 versus fed beagle dogs were also seen in a published 13-week toxicity study using a purified GTE containing less than 77% EGCG.[<a class="bk_pop" href="#CDR0000719335_rl_174_27">27</a>] However, in the follow-up NCI DCP-sponsored study in fed versus fasted dogs using several Polyphenon E formulations, no deaths occurred; numerous biochemical endpoints are currently being evaluated.</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 statistically significant inverse association between green tea consumption and prostate cancer risk in the three case control studies, but no association was found in the four <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000285673/" class="def">cohort studies</a>. 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_28">28</a>-<a class="bk_pop" href="#CDR0000719335_rl_174_32">32</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_33">33</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_33">33</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_34">34</a>,<a class="bk_pop" href="#CDR0000719335_rl_174_35">35</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 green tea catechins. </p></div><div id="CDR0000719335__203"><h4>Intervention studies</h4><div id="CDR0000719335__204"><h5>Prevention</h5><p id="CDR0000719335__205">In a single-center Italian study, 60 men diagnosed 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) were randomly assigned to receive green tea catechin <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000455334/" class="def">capsules</a> (600 mg green tea catechins 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 green tea catechin group were diagnosed with prostate cancer. After 1 year, nine men in the placebo group and one man in the green tea catechin group were diagnosed with prostate cancer (<i>P</i> < .01). These findings suggest that green tea catechins may help prevent prostate cancer in groups at high risk for the disease.[<a class="bk_pop" href="#CDR0000719335_rl_174_36">36</a>] In 2008, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044671/" class="def">follow-up</a> results to this study were published, indicating that the inhibitory effects of green tea catechins on prostate cancer progression were long-lasting.[<a class="bk_pop" href="#CDR0000719335_rl_174_37">37</a>] 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 men with either HGPIN or atypical small acinar proliferation (ASAP) who received a green tea catechin mixture (Polyphenon E, 200 mg, twice a day).[<a class="bk_pop" href="#CDR0000719335_rl_174_38">38</a>] </p></div><div id="CDR0000719335__206"><h5>Preoperative studies</h5><p id="CDR0000719335__562">In one study, 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. Bioavailable 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_39">39</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_40">40</a>] Ninety-three patients completed the intervention. Although there were no significant differences in markers of proliferation, apoptosis, and oxidation in the prostatectomy tissue, nuclear staining of NF-kappa B was significantly decreased in the specimens from men drinking green tea. 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 <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044195/" class="def">clinical study</a>, prostate cancer patients scheduled for radical prostatectomy consumed four Polyphenon E tablets containing tea polyphenols, including EGCG, daily (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_41">41</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_42">42</a>]</p></div><div id="CDR0000719335__565"><h5>Advanced prostate cancer</h5><p id="CDR0000719335__566">In a small, single-arm study, hormone-refractory prostate cancer patients received capsules of <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000389271/" class="def">green tea extract</a> twice daily (375 mg polyphenols daily) 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_43">43</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>
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<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 <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000445093/" class="def">toxicity</a> 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_44">44</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="http://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="http://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="http://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 of EGCG at single and multiple dosing schedule, and a duration of a few days to one year has been well documented in phase I/II clinical trials.[<a class="bk_pop" href="#CDR0000719335_rl_174_39">39</a>-<a class="bk_pop" href="#CDR0000719335_rl_174_49">49</a>] By conducting a phase I trial of oral green tea extract in adult patients with solid tumors, the authors reported that a safe dose of green tea extract 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_50">50</a>] The authors concluded that the side effects (neurological and gastrointestinal effects) 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_32">32</a>,<a class="bk_pop" href="#CDR0000719335_rl_174_33">33</a>,<a class="bk_pop" href="#CDR0000719335_rl_174_36">36</a>-<a class="bk_pop" href="#CDR0000719335_rl_174_38">38</a>,<a class="bk_pop" href="#CDR0000719335_rl_174_49">49</a>,<a class="bk_pop" href="#CDR0000719335_rl_174_51">51</a>] Adverse effects reported in these studies with a possible relationship to the study drug 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 more common when EGCG is administered in a fasting state. Gastrointestinal adverse effects were usually mild, seen most often in the fasting condition, and at the higher dose level. 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_41">41</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_41">41</a>,<a class="bk_pop" href="#CDR0000719335_rl_174_48">48</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_43">43</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_36">36</a>,<a class="bk_pop" href="#CDR0000719335_rl_174_38">38</a>] report long-term safety (1 year) 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_36">36</a>] administered approximately 300 mg EGCG per day for 1 year without any reported toxicities. However, the study had several limitations in that the agent stability and standardization were not subject to testing for catechin content throughout the duration of trial. Additionally, there were no objective measures or reports of compliance, agent-related toxicity, including liver toxicity monitoring and adherence-to-study agent. </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 men with HGPIN and ASAP who were not fasting. The study was conducted under a U.S. Federal Drug Administration Investigational New Drug application, using a standardized agent that contained 400 mg of EGCG. Plasma levels of catechins, "adherence to study" agent, and agent-related toxicity—including liver toxicity—were monitored throughout the study. More possible and probable grade 2 through grade 3 events in men who received Polyphenon 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. Notably, all grade 1 through grade 2 toxicities in this trial were determined from monthly comprehensive metabolic panels, including liver function tests, and not from subject-reported symptoms.[<a class="bk_pop" href="#CDR0000719335_rl_174_38">38</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_27">27</a>,<a class="bk_pop" href="#CDR0000719335_rl_174_47">47</a>,<a class="bk_pop" href="#CDR0000719335_rl_174_52">52</a>-<a class="bk_pop" href="#CDR0000719335_rl_174_54">54</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 GTE, 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 green tea extract capsules.[<a class="bk_pop" href="#CDR0000719335_rl_174_53">53</a>] The capsules contained Polyphenon 70A and 120 mg green tea extract. 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_54">54</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_27">27</a>] Therefore, 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, subjects should have liver function tests performed while 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. Mol Nutr Food Res 55 (6): 819-31, 2011. [<a href="https://pubmed.ncbi.nlm.nih.gov/21538856" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21538856</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_174_3">Trepardoux F, Delaveau P: [Origin of the word tea, and its extension to designate different hot infused drinks]. Rev Hist Pharm (Paris) 47 (322): 247-53, 1999. [<a href="https://pubmed.ncbi.nlm.nih.gov/11625528" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11625528</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_174_4">Deka A, Vita JA: Tea and cardiovascular disease. Pharmacol Res 64 (2): 136-45, 2011. [<a href="/pmc/articles/PMC3123419/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3123419</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/21477653" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21477653</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_174_5">Yang CS, Wang H, Li GX, et al.: Cancer prevention by tea: Evidence from laboratory studies. Pharmacol Res 64 (2): 113-22, 2011. [<a href="https://pubmed.ncbi.nlm.nih.gov/21397027" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21397027</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_174_6">Sang S, Lambert JD, Ho C, et al.: Green tea polyphenols. In: Coates PM, Betz JM, Blackman MR, et al., eds.: Encyclopedia of Dietary Supplements. 2nd ed. New York, NY: Informa Healthcare, 2010, pp 402-10.</div></li><li><div class="bk_ref" id="CDR0000719335_rl_174_7">Chuu CP, Chen RY, Kokontis JM, et al.: Suppression of androgen receptor signaling and prostate specific antigen expression by (-)-epigallocatechin-3-gallate in different progression stages of LNCaP prostate cancer cells. Cancer Lett 275 (1): 86-92, 2009. [<a href="/pmc/articles/PMC2980538/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2980538</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/18977589" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18977589</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_174_8">Thomas F, Holly JM, Persad R, et al.: Green tea extract (epigallocatechin-3-gallate) reduces efficacy of radiotherapy on prostate cancer cells. Urology 78 (2): 475.e15-21, 2011. [<a href="https://pubmed.ncbi.nlm.nih.gov/21676444" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21676444</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_174_9">Albrecht DS, Clubbs EA, Ferruzzi M, et al.: Epigallocatechin-3-gallate (EGCG) inhibits PC-3 prostate cancer cell proliferation via MEK-independent ERK1/2 activation. Chem Biol Interact 171 (1): 89-95, 2008. [<a href="https://pubmed.ncbi.nlm.nih.gov/17931610" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17931610</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_174_10">Luo KL, Luo JH, Yu YP: (-)-Epigallocatechin-3-gallate induces Du145 prostate cancer cell death via downregulation of inhibitor of DNA binding 2, a dominant negative helix-loop-helix protein. Cancer Sci 101 (3): 707-12, 2010. [<a href="/pmc/articles/PMC4040217/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4040217</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/20002680" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20002680</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_174_11">Rocha S, Generalov R, Pereira Mdo C, et al.: Epigallocatechin gallate-loaded polysaccharide nanoparticles for prostate cancer chemoprevention. Nanomedicine (Lond) 6 (1): 79-87, 2011. [<a href="https://pubmed.ncbi.nlm.nih.gov/21182420" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21182420</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_174_12">Sanna V, Pintus G, Roggio AM, et al.: Targeted biocompatible nanoparticles for the delivery of (-)-epigallocatechin 3-gallate to prostate cancer cells. J Med Chem 54 (5): 1321-32, 2011. [<a href="https://pubmed.ncbi.nlm.nih.gov/21306166" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21306166</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_174_13">Pandey M, Shukla S, Gupta S: Promoter demethylation and chromatin remodeling by green tea polyphenols leads to re-expression of GSTP1 in human prostate cancer cells. Int J Cancer 126 (11): 2520-33, 2010. [<a href="/pmc/articles/PMC2874465/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2874465</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19856314" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19856314</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_174_14">Thakur VS, Gupta K, Gupta S: Green tea polyphenols causes cell cycle arrest and apoptosis in prostate cancer cells by suppressing class I histone deacetylases. Carcinogenesis 33 (2): 377-84, 2012. [<a href="/pmc/articles/PMC3499108/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3499108</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/22114073" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22114073</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_174_15">Thakur VS, Gupta K, Gupta S: The chemopreventive and chemotherapeutic potentials of tea polyphenols. Curr Pharm Biotechnol 13 (1): 191-9, 2012. 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[<a href="/pmc/articles/PMC2408886/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2408886</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/18521193" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18521193</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_174_18">Siddiqui IA, Asim M, Hafeez BB, et al.: Green tea polyphenol EGCG blunts androgen receptor function in prostate cancer. FASEB J 25 (4): 1198-207, 2011. [<a href="/pmc/articles/PMC3058706/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3058706</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/21177307" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21177307</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_174_19">Adhami VM, Siddiqui IA, Sarfaraz S, et al.: Effective prostate cancer chemopreventive intervention with green tea polyphenols in the TRAMP model depends on the stage of the disease. Clin Cancer Res 15 (6): 1947-53, 2009. 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[<a href="https://pubmed.ncbi.nlm.nih.gov/14512803" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 14512803</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_174_32">Montague JA, Butler LM, Wu AH, et al.: Green and black tea intake in relation to prostate cancer risk among Singapore Chinese. Cancer Causes Control 23 (10): 1635-41, 2012. [<a href="/pmc/articles/PMC3695613/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3695613</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/22864870" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22864870</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_174_33">Ito K: Prostate cancer in Asian men. Nat Rev Urol 11 (4): 197-212, 2014. 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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_40">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_41">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_42">Nguyen MM, Ahmann FR, Nagle RB, et al.: Randomized, double-blind, placebo-controlled trial of polyphenon E in prostate cancer patients before prostatectomy: evaluation of potential chemopreventive activities. Cancer Prev Res (Phila) 5 (2): 290-8, 2012. [<a href="/pmc/articles/PMC3273617/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3273617</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/22044694" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22044694</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_174_43">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_44">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_45">Chow HH, Cai Y, Alberts DS, et al.: Phase I pharmacokinetic study of tea polyphenols following single-dose administration of epigallocatechin gallate and polyphenon E. Cancer Epidemiol Biomarkers Prev 10 (1): 53-8, 2001. [<a href="https://pubmed.ncbi.nlm.nih.gov/11205489" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11205489</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_174_46">Chow HH, Hakim IA, Vining DR, et al.: Effects of dosing condition on the oral bioavailability of green tea catechins after single-dose administration of Polyphenon E in healthy individuals. Clin Cancer Res 11 (12): 4627-33, 2005. [<a href="https://pubmed.ncbi.nlm.nih.gov/15958649" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15958649</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_174_47">Chow HH, Cai Y, Hakim IA, et al.: Pharmacokinetics and safety of green tea polyphenols after multiple-dose administration of epigallocatechin gallate and polyphenon E in healthy individuals. Clin Cancer Res 9 (9): 3312-9, 2003. [<a href="https://pubmed.ncbi.nlm.nih.gov/12960117" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12960117</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_174_48">Wang P, Aronson WJ, Huang M, et al.: Green tea polyphenols and metabolites in prostatectomy tissue: implications for cancer prevention. Cancer Prev Res (Phila) 3 (8): 985-93, 2010. [<a href="/pmc/articles/PMC3163459/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3163459</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/20628004" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20628004</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_174_49">Lee MJ, Maliakal P, Chen L, et al.: Pharmacokinetics of tea catechins after ingestion of green tea and (-)-epigallocatechin-3-gallate by humans: formation of different metabolites and individual variability. Cancer Epidemiol Biomarkers Prev 11 (10 Pt 1): 1025-32, 2002. [<a href="https://pubmed.ncbi.nlm.nih.gov/12376503" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12376503</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_174_50">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_51">Yuan JM: Cancer prevention by green tea: evidence from epidemiologic studies. Am J Clin Nutr 98 (6 Suppl): 1676S-1681S, 2013. [<a href="/pmc/articles/PMC3831544/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3831544</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/24172305" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24172305</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_174_52">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_53">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_54">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 carotenoid, a natural pigment made by plants, which 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>] 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 it is in raw tomatoes.[<a class="bk_pop" href="#CDR0000719335_rl_16_3">3</a>] When <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044100/" class="def">ingested</a>, lycopene is broken down into a number of metabolites and is thought to have various <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044510/" class="def">biological</a> functions, 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_4">4</a>]</p><p id="CDR0000719335__6">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_5">5</a>] Results of a <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045858/" class="def">randomized</a> study published in 2005 revealed 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_6">6</a>] According to one study,[<a class="bk_pop" href="#CDR0000719335_rl_16_7">7</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 same study found that combining olive oil, but not sunflower oil, with tomatoes resulted in greater plasma antioxidant activity.</p><p id="CDR0000719335__7">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, although some interventional studies have shown mixed results.[<a class="bk_pop" href="#CDR0000719335_rl_16_3">3</a>] 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_8">8</a>] 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_9">9</a>] However, epidemiological studies reported to date have yielded inconsistent findings regarding lycopene's potential in reducing cancer risk. 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 thus have not been definitive.[<a class="bk_pop" href="#CDR0000719335_rl_16_2">2</a>,<a class="bk_pop" href="#CDR0000719335_rl_16_10">10</a>]</p><p id="CDR0000719335__8">In 2004, the FDA received two petitions for qualified health claims regarding tomatoes, lycopene, and reduced cancer risk. In a 2007 review, the FDA concluded there was not enough evidence to support a claim that lycopene helps reduce cancer risk. The FDA found there was no evidence of a link between tomato consumption and lung, colorectal, breast, cervical, or endometrial cancers, and there was limited evidence for an association between tomato consumption and reduced risks of prostate, ovarian, gastric, and pancreatic cancers.[<a class="bk_pop" href="#CDR0000719335_rl_16_11">11</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">Many <i>in vitro</i> studies have been conducted examining a link between lycopene and prostate cancer. </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_12">12</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 S phase of the cell cycle, suggesting that lycopene may lower cell proliferation by altering cell-cycle progression. Moreover, apo-12’-lycopenal, a lycopene <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000462687/" class="def">metabolite</a>, also reduced prostate cancer cell proliferation and may also modulate cell-cycle progression.[<a class="bk_pop" href="#CDR0000719335_rl_16_13">13</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_14">14</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 while treating cells with a combination of the PPARγ antagonist and lycopene decreased cell proliferation.[<a class="bk_pop" href="#CDR0000719335_rl_16_15">15</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_16">16</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_17">17</a>]</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_18">18</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_19">19</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 (NMU)/testosterone-induced prostate <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046487/" class="def">carcinogenesis</a> 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_20">20</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> studies. 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_21">21</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_22">22</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_18">18</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 risks of prostate cancer.[<a class="bk_pop" href="#CDR0000719335_rl_16_11">11</a>-<a class="bk_pop" href="#CDR0000719335_rl_16_16">16</a>] Prospective and case control studies 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_11">11</a>,<a class="bk_pop" href="#CDR0000719335_rl_16_18">18</a>-<a class="bk_pop" href="#CDR0000719335_rl_16_21">21</a>,<a class="bk_pop" href="#CDR0000719335_rl_16_23">23</a>] while other studies have failed to demonstrate such a connection.[<a class="bk_pop" href="#CDR0000719335_rl_16_24">24</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 (KIHD) study in Finland. In this prospective <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000285673/" class="def">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_25">25</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_26">26</a>] A 2013 meta-analysis, including four of five cohort studies from the 2004 meta-analysis, two new meta-analyses and three <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000348989/" class="def">case-control studies</a> from the previous study plus eight new ones, reported less convincing evidence for risk reduction.[<a class="bk_pop" href="#CDR0000719335_rl_16_27">27</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 tomatoes products, the RR was 0.85 (95% CI, 0.69–1.06). These authors concluded that tomato 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 up 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_28">28</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_29">29</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_30">30</a>]</p><p id="CDR0000719335__266">The variability in these epidemiological study results may be related to lycopene source; exposure misclassification; 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. 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><p id="CDR0000719335__38">Healthy males participated in a crossover design study that attempted to differentiate the effects of tomatoes from those of lycopene. After study entry, the participants consumed their usual diet for 1 week followed by a 2-week washout period on a lycopene-free diet. Next, they were randomly assigned to consume either yellow tomato paste (0 mg/day lycopene) (Group 1) or red tomato paste (16 mg/day lycopene) (Group 2) for 1 week as part of their regular diets, followed by a second 2-week washout period. Then, the participants in Group 1 crossed over to red tomato paste, and the participants in Group 2 crossed over to yellow tomato paste for 1 week as part of their regular diets, followed by a third 2-week washout period. Finally, the participants in Group 1 took a <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000455334/" class="def">capsule</a> of lycopene (16 mg/day) and the participants in Group 2 took a placebo daily for 1 week. Circulating lycopene levels increased only after consumption of red tomato paste and the lycopene capsules. Changes in serum PSA level, antioxidant status, and IGF-1 level were not modified by the consumption of tomato paste and lycopene. When prostate cancer cells were treated <i>in vitro</i> with sera collected from participants after red tomato paste consumption, IGF binding protein-3 (IGFBP-3) and the ratio of Bax to <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000613897/" class="def">Bcl2</a> were up regulated, and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000729820/" class="def">cyclin-D1</a>, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045813/" class="def">p53</a>, and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000729822/" class="def">Nrf-2</a> were down regulated compared with expression levels obtained using sera taken after the first washout period. Intermediate <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000537335/" class="def">gene expression</a> changes were observed using sera collected from participants after yellow tomato paste consumption. These findings suggest that lycopene may not be the only factor responsible for the protective effects of tomatoes.[<a class="bk_pop" href="#CDR0000719335_rl_16_31">31</a>]</p><p id="CDR0000719335__39">In another study, the effect of tomato sauce on apoptosis in <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046509/" class="def">benign prostate 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_32">32</a>]</p><p id="CDR0000719335__40">In a third study, patients with <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000386205/" class="def">high-grade</a>
|
|
<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 those 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 than in patients who had received lycopene (6/20 vs. 2/20). These findings suggest that lycopene may be effective in preventing HGPIN from progressing to prostate cancer.[<a class="bk_pop" href="#CDR0000719335_rl_16_33">33</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. These findings suggest that, although lycopene supplements may be safe to take for at least 4 months, they may not affect PSA levels.[<a class="bk_pop" href="#CDR0000719335_rl_16_34">34</a>]</p><p id="CDR0000719335__462">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_23">23</a>]</p><p id="CDR0000719335__41">Other studies have examined the potential therapeutic effect of lycopene-containing products in patients with prostate cancer. The effects of lycopene supplementation on prostate tissue and prostate cancer <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045618/" class="def">biomarkers</a> were investigated in patients with <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045754/" class="def">localized</a> prostate cancer in a 2002 <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045838/" class="def">pilot study</a>. Patients received lycopene supplements (30mg/day) or no intervention twice daily for 3 weeks prior to <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046549/" class="def">radical prostatectomy</a>. Patients who received the lycopene supplements had smaller tumors and lower serum PSA levels than patients who did not receive the supplements. These results suggest that lycopene may be beneficial in prostate cancer treatment.[<a class="bk_pop" href="#CDR0000719335_rl_16_35">35</a>] A 2006 study investigated whether lycopene supplements (10 mg/day) would affect <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000651206/" class="def">PSA velocity</a> in patients with localized prostate cancer over the course of 1 year of treatment. There was a statistically significant decrease in PSA velocity following lycopene treatment as well as a large, but not statistically significant, increase in PSA <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000306523/" class="def">doubling time</a>.[<a class="bk_pop" href="#CDR0000719335_rl_16_36">36</a>]</p><p id="CDR0000719335__264">In a phase II, randomized, placebo-controlled trial,[<a class="bk_pop" href="#CDR0000719335_rl_16_37">37</a>] 45 men with clinically localized prostate cancer received either 15, 30, or 45 mg of lycopene 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, similar to levels observed in previous studies in men with prostate cancer. At the 30 mg lycopene dose level, a moderate decrease in mean free testosterone and a significant increase in mean plasma estradiol was observed (24.90 [+/−7.94] to 32.30 [+/−7.93]; <i>P</i> = .02). In addition, significant increase in serum sex hormone-binding globulin (SHBG) (39.31 [+/−16.04] to 45.67 [+/−19.83]; <i>P</i> = .022) and total estradiol (27.54 pmol/L [SD 7.82] to 37.64 pmol/L [SD 12.65]; <i>P</i> = .006) was observed in the 45 mg/day lycopene-supplemented arm, 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, where 100% of the subjects observed an increase. These changes were not statistically significant, 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_37">37</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/day). 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_38">38</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/day 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_39">39</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_40">40</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/day) for at least 4 months. Only one patient in this study exhibited a decrease in PSA level, suggesting that lycopene may not be effective <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044737/" class="def">therapy</a> for patients with androgen-independent prostate cancer. A number of participants experienced gastrointestinal side effects after eating the tomato paste or drinking the tomato juice.[<a class="bk_pop" href="#CDR0000719335_rl_16_41">41</a>]</p><p id="CDR0000719335__45">In one 2011 study that explored the effects of lycopene and fish oil supplements on gene expression, men with low-risk prostate cancer were randomly assigned to receive lycopene (30 mg of lycopene/day), fish oil (3 g of fish oil capsules/day), or a placebo daily for 90 days. Gene expression analysis showed no statistically significant differential expression of individual genes associated with the consumption of fish oil or lycopene supplements. However, pathway analysis revealed that an <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044072/" class="def">oxidative stress</a> response pathway was significantly modulated following lycopene or fish oil supplement use compared with placebo (fish oil: <i>P</i> = .01, lycopene: <i>P</i> = .001).[<a class="bk_pop" href="#CDR0000719335_rl_16_42">42</a>]</p></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="http://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="http://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">Lycopene has been well tolerated in a number of clinical trials involving prostate cancer patients.[<a class="bk_pop" href="#CDR0000719335_rl_16_31">31</a>,<a class="bk_pop" href="#CDR0000719335_rl_16_33">33</a>,<a class="bk_pop" href="#CDR0000719335_rl_16_34">34</a>,<a class="bk_pop" href="#CDR0000719335_rl_16_36">36</a>,<a class="bk_pop" href="#CDR0000719335_rl_16_39">39</a>] 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_41">41</a>] and, in one study, the symptoms resolved when lycopene was taken with meals.[<a class="bk_pop" href="#CDR0000719335_rl_16_40">40</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_38">38</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 Generally Recognized as Safe (GRAS).[<a class="bk_pop" href="#CDR0000719335_rl_16_43">43</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. In: Coates PM, Betz JM, Blackman MR, et al., eds.: Encyclopedia of Dietary Supplements. 2nd ed. New York, NY: Informa Healthcare, 2010, pp 504-17.</div></li><li><div class="bk_ref" id="CDR0000719335_rl_16_2">van Breemen RB, Pajkovic N: Multitargeted therapy of cancer by lycopene. Cancer Lett 269 (2): 339-51, 2008. [<a href="/pmc/articles/PMC2615641/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2615641</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/18585855" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18585855</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_16_3">Mordente A, Guantario B, Meucci E, et al.: Lycopene and cardiovascular diseases: an update. Curr Med Chem 18 (8): 1146-63, 2011. [<a href="https://pubmed.ncbi.nlm.nih.gov/21291369" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21291369</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_16_4">Mein JR, Lian F, Wang XD: Biological activity of lycopene metabolites: implications for cancer prevention. Nutr Rev 66 (12): 667-83, 2008. [<a href="/pmc/articles/PMC6824483/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC6824483</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19019036" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19019036</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_16_5">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_6">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_7">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_8">Arab L, Steck S: Lycopene and cardiovascular disease. Am J Clin Nutr 71 (6 Suppl): 1691S-5S; discussion 1696S-7S, 2000. [<a href="https://pubmed.ncbi.nlm.nih.gov/10837319" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10837319</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_16_9">Khan N, Afaq F, Mukhtar H: Cancer chemoprevention through dietary antioxidants: progress and promise. Antioxid Redox Signal 10 (3): 475-510, 2008. [<a href="https://pubmed.ncbi.nlm.nih.gov/18154485" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18154485</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_16_10">Ilic D, Forbes KM, Hassed C: Lycopene for the prevention of prostate cancer. Cochrane Database Syst Rev (11): CD008007, 2011. [<a href="/pmc/articles/PMC8939370/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC8939370</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/22071840" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22071840</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_16_11">Kavanaugh CJ, Trumbo PR, Ellwood KC: The U.S. Food and Drug Administration's evidence-based review for qualified health claims: tomatoes, lycopene, and cancer. J Natl Cancer Inst 99 (14): 1074-85, 2007. [<a href="https://pubmed.ncbi.nlm.nih.gov/17623802" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17623802</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_16_12">Obermüller-Jevic UC, Olano-Martin E, Corbacho AM, et al.: Lycopene inhibits the growth of normal human prostate epithelial cells in vitro. J Nutr 133 (11): 3356-60, 2003. [<a href="https://pubmed.ncbi.nlm.nih.gov/14608044" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 14608044</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_16_13">Ford NA, Elsen AC, Zuniga K, et al.: Lycopene and apo-12'-lycopenal reduce cell proliferation and alter cell cycle progression in human prostate cancer cells. Nutr Cancer 63 (2): 256-63, 2011. [<a href="https://pubmed.ncbi.nlm.nih.gov/21207319" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21207319</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_16_14">Palozza P, Colangelo M, Simone R, et al.: Lycopene induces cell growth inhibition by altering mevalonate pathway and Ras signaling in cancer cell lines. Carcinogenesis 31 (10): 1813-21, 2010. [<a href="https://pubmed.ncbi.nlm.nih.gov/20699249" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20699249</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_16_15">Yang CM, Lu IH, Chen HY, et al.: Lycopene inhibits the proliferation of androgen-dependent human prostate tumor cells through activation of PPARγ-LXRα-ABCA1 pathway. J Nutr Biochem 23 (1): 8-17, 2012. [<a href="https://pubmed.ncbi.nlm.nih.gov/21334870" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21334870</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_16_16">Zhang X, Wang Q, Neil B, et al.: Effect of lycopene on androgen receptor and prostate-specific antigen velocity. Chin Med J (Engl) 123 (16): 2231-6, 2010. [<a href="https://pubmed.ncbi.nlm.nih.gov/20819671" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20819671</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_16_17">Qiu X, Yuan Y, Vaishnav A, et al.: Effects of lycopene on protein expression in human primary prostatic epithelial cells. Cancer Prev Res (Phila) 6 (5): 419-27, 2013. [<a href="/pmc/articles/PMC3644332/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3644332</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/23483004" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23483004</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_16_18">Tang Y, Parmakhtiar B, Simoneau AR, et al.: Lycopene enhances docetaxel's effect in castration-resistant prostate cancer associated with insulin-like growth factor I receptor levels. Neoplasia 13 (2): 108-19, 2011. [<a href="/pmc/articles/PMC3033590/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3033590</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/21403837" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21403837</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_16_19">Konijeti R, Henning S, Moro A, et al.: Chemoprevention of prostate cancer with lycopene in the TRAMP model. Prostate 70 (14): 1547-54, 2010. [<a href="/pmc/articles/PMC2930120/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2930120</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/20687227" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20687227</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_16_20">Mossine VV, Chopra P, Mawhinney TP: Interaction of tomato lycopene and ketosamine against rat prostate tumorigenesis. Cancer Res 68 (11): 4384-91, 2008. [<a href="https://pubmed.ncbi.nlm.nih.gov/18519700" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18519700</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_16_21">Yang CM, Yen YT, Huang CS, et al.: Growth inhibitory efficacy of lycopene and β-carotene against androgen-independent prostate tumor cells xenografted in nude mice. Mol Nutr Food Res 55 (4): 606-12, 2011. [<a href="https://pubmed.ncbi.nlm.nih.gov/21462328" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21462328</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_16_22">Yang CM, Lu YL, Chen HY, et al.: Lycopene and the LXRα agonist T0901317 synergistically inhibit the proliferation of androgen-independent prostate cancer cells via the PPARγ-LXRα-ABCA1 pathway. J Nutr Biochem 23 (9): 1155-62, 2012. [<a href="https://pubmed.ncbi.nlm.nih.gov/22137263" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22137263</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_16_23">Mariani S, Lionetto L, Cavallari M, et al.: Low prostate concentration of lycopene is associated with development of prostate cancer in patients with high-grade prostatic intraepithelial neoplasia. Int J Mol Sci 15 (1): 1433-40, 2014. [<a href="/pmc/articles/PMC3907878/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3907878</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/24451130" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24451130</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_16_24">Kristal AR, Till C, Platz EA, et al.: Serum lycopene concentration and prostate cancer risk: results from the Prostate Cancer Prevention Trial. Cancer Epidemiol Biomarkers Prev 20 (4): 638-46, 2011. [<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_25">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_26">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_27">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_28">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_29">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_30">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_31">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_32">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_33">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_34">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_35">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_36">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_37">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_38">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_39">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_40">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_41">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_42">Magbanua MJ, Roy R, Sosa EV, et al.: Gene expression and biological pathways in tissue of men with prostate cancer in a randomized clinical trial of lycopene and fish oil supplementation. PLoS One 6 (9): e24004, 2011. [<a href="/pmc/articles/PMC3164676/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3164676</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/21912659" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21912659</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_16_43">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 19, 2016.</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 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 citrus pectin-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>] Citrus pectin 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 citrus pectins.[<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; citrus pectin (CP), Pectasol (PeS, a <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000373932/" class="def">dietary supplement</a> containing modified citrus pectin), 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="http://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="http://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 19, 2016.</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 bioactive <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000422394/" class="def">compounds</a>, including catechin <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000463152/" class="def">phenolics</a>, related <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000330168/" class="def">flavonoids</a>, and anthocyanins, some of which have <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000043997/" class="def">antioxidant</a> activity.</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> anticancer 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, 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 a number of bioactive <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000422394/" class="def">compounds</a>, including phenolics, flavonoids, and ellagitannins, and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045787/" class="def">minerals</a> such as <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044344/" class="def">potassium</a>, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000373087/" class="def">magnesium</a>, and <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044731/" class="def">sodium</a>. Arils are mainly composed of water and also contain phenolics and flavonoids. Anthocyanins, which are flavonoid present in arils, are responsible for the fruit's and its juice’s red color.[<a class="bk_pop" href="#CDR0000719335_rl_162_3">3</a>] The majority of antioxidant activity comes from ellagitannins.[<a class="bk_pop" href="#CDR0000719335_rl_162_4">4</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_5">5</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_6">6</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 <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000256573/" class="def">polyphenols</a> 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 (0.3mg/mouse/dose). Ellagic acid was detected in the prostate following intraperitoneal, but not oral, administration of pomegranate extract (0.8mg/mouse/dose).[<a class="bk_pop" href="#CDR0000719335_rl_162_7">7</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_8">8</a>-<a class="bk_pop" href="#CDR0000719335_rl_162_11">11</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_9">9</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 suggest that punicic acid may activate apoptosis by a caspase-dependent pathway.[<a class="bk_pop" href="#CDR0000719335_rl_162_9">9</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_10">10</a>,<a class="bk_pop" href="#CDR0000719335_rl_162_12">12</a>,<a class="bk_pop" href="#CDR0000719335_rl_162_13">13</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 ellagic acid (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_10">10</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_13">13</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 anti-carcinogenic 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_14">14</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_12">12</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 suggest that PJ may be beneficial in slowing down or preventing cancer cell metastasis.[<a class="bk_pop" href="#CDR0000719335_rl_162_15">15</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_13">13</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_7">7</a>,<a class="bk_pop" href="#CDR0000719335_rl_162_16">16</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_8">8</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 20 weeks of age, whereas just 30% and 20% of the mice that received 0.1% and 0.2% PJ, respectively, developed tumors. By 34 weeks of age, 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 to the water-fed mice.<div class="milestone-end"></div>[<a class="bk_pop" href="#CDR0000719335_rl_162_17">17</a>]</p></div></div><div id="CDR0000719335__99"><h3>Human Studies</h3><p id="CDR0000719335__100">In a study reported in 2006, researchers observed the effects of PJ on PSA values in prostate cancer patients (N = 48) who had rising PSA levels following treatment with <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>. The study participants drank 8 ounces of PJ daily (570 mg/day total polyphenol gallic acid equivalents) for up to 33 months. Drinking PJ was associated with statistically significant increases in PSADT. After 33 months of follow-up, the median PSADT increased from 11.5 months to 28.7 months (<i>P</i> < .001). In addition, LNCaP cells were treated <i>in vitro</i> with the subjects’ serum before and after the PJ intervention. Results of the <i>in vitro</i> experiments showed a decrease in cell growth and an increase in apoptosis following PJ treatment.[<a class="bk_pop" href="#CDR0000719335_rl_162_18">18</a>]</p><p id="CDR0000719335__253">A phase II study evaluated 1-g and 3-g doses of pomegranate extract in 104 men with rising PSA values following initial therapy for <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045754/" class="def">localized</a> prostate cancer.[<a class="bk_pop" href="#CDR0000719335_rl_162_19">19</a>] The study reported that pomegranate extract was associated with an increase of at least 6 months in PSADT in both treatment arms, without adverse effects. However, a phase III placebo-controlled trial of 183 patients who were randomly assigned to the pomegranate juice, pomegranate extract, or placebo did not significantly prolong PSADT in prostate cancer patients with rising PSA after primary therapy.[<a class="bk_pop" href="#CDR0000719335_rl_162_20">20</a>] Some data from this study suggest that a subgroup analysis should be done to further investigate a potential unique sensitivity.</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="http://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="http://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="http://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="http://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_18">18</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_21">21</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 19, 2016. [<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">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_6">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_7">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_8">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_9">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_10">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_11">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_12">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_13">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_14">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_15">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_16">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_17">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_18">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_19">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_20">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_21">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 <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045023/" class="def">Vitamin E</a> Cancer <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000439419/" class="def">Prevention</a> 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 vitamin E 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 selenoprotein P 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> (MeSeA) 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 how effective selenium is 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 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 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 to 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 to 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 suggests 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 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 selenoprotein P gene (SEPP1) 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 of the gene encoding the enzyme manganese superoxide dismutase (SOD2) a patient had. For men with the 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 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 <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044671/" class="def">Follow-Up</a> 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 the end of the study. Compared to 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 LDL 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 selenized 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-selenium 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 of 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 selenized yeast had been used in previous studies. SELECT researchers chose selenomethionine because it was the major component of selenized 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 over product consistency with high-selenium 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>]</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="http://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="http://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="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></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 been conducted comparing effects of individual isoflavones with isoflavone combinations on prostate cancer cells. In one such 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 <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000407760/" class="def">extract</a> 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 suggest 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; comprised of 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 out of 25 men in the isoflavone group developed prostate cancer, compared with 16 out 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. Following 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 was inversely correlated with changes in serum PSA, compared with the placebo arm. </p><p id="CDR0000719335__281">In 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="http://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="http://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="http://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. Lymphat Res Biol 8 (1): 89-98, 2010. [<a href="/pmc/articles/PMC2883528/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2883528</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/20235891" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20235891</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_163_2">Omoni AO, Aluko RE: Soybean foods and their benefits: potential mechanisms of action. Nutr Rev 63 (8): 272-83, 2005. [<a href="https://pubmed.ncbi.nlm.nih.gov/16190314" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16190314</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_163_3">Jian L: Soy, isoflavones, and prostate cancer. Mol Nutr Food Res 53 (2): 217-26, 2009. [<a href="https://pubmed.ncbi.nlm.nih.gov/18985655" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18985655</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_163_4">Messina M: A brief historical overview of the past two decades of soy and isoflavone research. J Nutr 140 (7): 1350S-4S, 2010. [<a href="https://pubmed.ncbi.nlm.nih.gov/20484551" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20484551</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_163_5">Andres S, Abraham K, Appel KE, et al.: Risks and benefits of dietary isoflavones for cancer. Crit Rev Toxicol 41 (6): 463-506, 2011. [<a href="https://pubmed.ncbi.nlm.nih.gov/21438720" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21438720</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_163_6">Messina M: Isoflavones. In: Coates PM, Betz JM, Blackman MR, et al., eds.: Encyclopedia of Dietary Supplements. 2nd ed. New York, NY: Informa Healthcare, 2010, pp 439-49.</div></li><li><div class="bk_ref" id="CDR0000719335_rl_163_7">Messina M: Insights gained from 20 years of soy research. J Nutr 140 (12): 2289S-2295S, 2010. [<a href="https://pubmed.ncbi.nlm.nih.gov/20980639" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20980639</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_163_8">Bektic J, Guggenberger R, Eder IE, et al.: Molecular effects of the isoflavonoid genistein in prostate cancer. Clin Prostate Cancer 4 (2): 124-9, 2005. [<a href="https://pubmed.ncbi.nlm.nih.gov/16197614" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16197614</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_163_9">Perabo FG, Von Löw EC, Ellinger J, et al.: Soy isoflavone genistein in prevention and treatment of prostate cancer. Prostate Cancer Prostatic Dis 11 (1): 6-12, 2008. [<a href="https://pubmed.ncbi.nlm.nih.gov/17923857" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17923857</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_163_10">Swami S, Krishnan AV, Moreno J, et al.: Inhibition of prostaglandin synthesis and actions by genistein in human prostate cancer cells and by soy isoflavones in prostate cancer patients. Int J Cancer 124 (9): 2050-9, 2009. [<a href="/pmc/articles/PMC4777303/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4777303</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19127598" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19127598</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_163_11">Rabiau N, Kossaï M, Braud M, et al.: Genistein and daidzein act on a panel of genes implicated in cell cycle and angiogenesis by polymerase chain reaction arrays in human prostate cancer cell lines. Cancer Epidemiol 34 (2): 200-6, 2010. [<a href="https://pubmed.ncbi.nlm.nih.gov/20097631" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20097631</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_163_12">Ajdžanović V, Mojić M, Maksimović-Ivanić D, et al.: Membrane fluidity, invasiveness and dynamic phenotype of metastatic prostate cancer cells after treatment with soy isoflavones. J Membr Biol 246 (4): 307-14, 2013. [<a href="https://pubmed.ncbi.nlm.nih.gov/23417033" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23417033</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_163_13">Hsu A, Bray TM, Helferich WG, et al.: Differential effects of whole soy extract and soy isoflavones on apoptosis in prostate cancer cells. Exp Biol Med (Maywood) 235 (1): 90-7, 2010. [<a href="/pmc/articles/PMC4125131/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4125131</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/20404023" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20404023</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_163_14">Kumar R, Verma V, Jain A, et al.: Synergistic chemoprotective mechanisms of dietary phytoestrogens in a select combination against prostate cancer. J Nutr Biochem 22 (8): 723-31, 2011. [<a href="https://pubmed.ncbi.nlm.nih.gov/21062672" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21062672</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_163_15">Ide H, Tokiwa S, Sakamaki K, et al.: Combined inhibitory effects of soy isoflavones and curcumin on the production of prostate-specific antigen. Prostate 70 (10): 1127-33, 2010. [<a href="https://pubmed.ncbi.nlm.nih.gov/20503397" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20503397</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_163_16">Wang J, Eltoum IE, Lamartiniere CA: Genistein alters growth factor signaling in transgenic prostate model (TRAMP). Mol Cell Endocrinol 219 (1-2): 171-80, 2004. [<a href="https://pubmed.ncbi.nlm.nih.gov/15149738" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15149738</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_163_17">El Touny LH, Banerjee PP: Identification of a biphasic role for genistein in the regulation of prostate cancer growth and metastasis. Cancer Res 69 (8): 3695-703, 2009. [<a href="/pmc/articles/PMC2669842/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2669842</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19351854" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19351854</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_163_18">Lakshman M, Xu L, Ananthanarayanan V, et al.: Dietary genistein inhibits metastasis of human prostate cancer in mice. Cancer Res 68 (6): 2024-32, 2008. [<a href="https://pubmed.ncbi.nlm.nih.gov/18339885" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18339885</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_163_19">Nakamura H, Wang Y, Kurita T, et al.: Genistein increases epidermal growth factor receptor signaling and promotes tumor progression in advanced human prostate cancer. PLoS One 6 (5): e20034, 2011. [<a href="/pmc/articles/PMC3095647/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3095647</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/21603581" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21603581</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_163_20">Raffoul JJ, Banerjee S, Che M, et al.: Soy isoflavones enhance radiotherapy in a metastatic prostate cancer model. Int J Cancer 120 (11): 2491-8, 2007. [<a href="https://pubmed.ncbi.nlm.nih.gov/17304503" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17304503</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_163_21">Hwang YW, Kim SY, Jee SH, et al.: Soy food consumption and risk of prostate cancer: a meta-analysis of observational studies. Nutr Cancer 61 (5): 598-606, 2009. [<a href="https://pubmed.ncbi.nlm.nih.gov/19838933" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19838933</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_163_22">van Die MD, Bone KM, Williams SG, et al.: Soy and soy isoflavones in prostate cancer: a systematic review and meta-analysis of randomized controlled trials. BJU Int 113 (5b): E119-30, 2014. [<a href="https://pubmed.ncbi.nlm.nih.gov/24053483" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24053483</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_163_23">Jackson MD, McFarlane-Anderson ND, Simon GA, et al.: Urinary phytoestrogens and risk of prostate cancer in Jamaican men. Cancer Causes Control 21 (12): 2249-57, 2010. [<a href="https://pubmed.ncbi.nlm.nih.gov/20924663" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20924663</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_163_24">Maskarinec G, Morimoto Y, Hebshi S, et al.: Serum prostate-specific antigen but not testosterone levels decrease in a randomized soy intervention among men. Eur J Clin Nutr 60 (12): 1423-9, 2006. [<a href="https://pubmed.ncbi.nlm.nih.gov/16775579" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16775579</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_163_25">Hamilton-Reeves JM, Rebello SA, Thomas W, et al.: Effects of soy protein isolate consumption on prostate cancer biomarkers in men with HGPIN, ASAP, and low-grade prostate cancer. Nutr Cancer 60 (1): 7-13, 2008. [<a href="https://pubmed.ncbi.nlm.nih.gov/18444130" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18444130</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_163_26">Miyanaga N, Akaza H, Hinotsu S, et al.: Prostate cancer chemoprevention study: an investigative randomized control study using purified isoflavones in men with rising prostate-specific antigen. Cancer Sci 103 (1): 125-30, 2012. [<a href="https://pubmed.ncbi.nlm.nih.gov/21988617" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21988617</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_163_27">Engelhardt PF, Riedl CR: Effects of one-year treatment with isoflavone extract from red clover on prostate, liver function, sexual function, and quality of life in men with elevated PSA levels and negative prostate biopsy findings. Urology 71 (2): 185-90; discussion 190, 2008. [<a href="https://pubmed.ncbi.nlm.nih.gov/18308079" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18308079</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_163_28">Kwan W, Duncan G, Van Patten C, et al.: A phase II trial of a soy beverage for subjects without clinical disease with rising prostate-specific antigen after radical radiation for prostate cancer. Nutr Cancer 62 (2): 198-207, 2010. [<a href="https://pubmed.ncbi.nlm.nih.gov/20099194" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20099194</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_163_29">Pendleton JM, Tan WW, Anai S, et al.: Phase II trial of isoflavone in prostate-specific antigen recurrent prostate cancer after previous local therapy. BMC Cancer 8: 132, 2008. [<a href="/pmc/articles/PMC2394534/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2394534</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/18471323" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18471323</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_163_30">deVere White RW, Hackman RM, Soares SE, et al.: Effects of a genistein-rich extract on PSA levels in men with a history of prostate cancer. Urology 63 (2): 259-63, 2004. [<a href="https://pubmed.ncbi.nlm.nih.gov/14972467" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 14972467</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_163_31">deVere White RW, Tsodikov A, Stapp EC, et al.: Effects of a high dose, aglycone-rich soy extract on prostate-specific antigen and serum isoflavone concentrations in men with localized prostate cancer. Nutr Cancer 62 (8): 1036-43, 2010. [<a href="/pmc/articles/PMC2993162/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2993162</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/21058191" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21058191</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_163_32">Lazarevic B, Boezelijn G, Diep LM, et al.: Efficacy and safety of short-term genistein intervention in patients with localized prostate cancer prior to radical prostatectomy: a randomized, placebo-controlled, double-blind Phase 2 clinical trial. Nutr Cancer 63 (6): 889-98, 2011. [<a href="https://pubmed.ncbi.nlm.nih.gov/21714686" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21714686</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_163_33">Hamilton-Reeves JM, Banerjee S, Banerjee SK, et al.: Short-term soy isoflavone intervention in patients with localized prostate cancer: a randomized, double-blind, placebo-controlled trial. PLoS One 8 (7): e68331, 2013. [<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. [<a href="/pmc/articles/PMC2435485/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2435485</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/18001210" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18001210</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_163_35">Kumar NB, Krischer JP, Allen K, et al.: Safety of purified isoflavones in men with clinically localized prostate cancer. Nutr Cancer 59 (2): 169-75, 2007. [<a href="/pmc/articles/PMC2442460/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2442460</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/18001211" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18001211</span></a>]</div></li><li><div class="bk_ref" id="CDR0000719335_rl_163_36">Kumar NB, Kang L, Pow-Sang J, et al.: Results of a randomized phase I dose-finding trial of several doses of isoflavones in men with localized prostate cancer: administration prior to radical prostatectomy. J Soc Integr Oncol 8 (1): 3-13, 2010. [<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 fortified dairy products, fatty fish, fish liver oil, and eggs. 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>Promoting <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>Improving 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>Helping to reduce <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044042/" class="def">inflammation</a>.</div></li><li class="half_rhythm"><div>Helping 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 ng/mL) 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.</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_20">20</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_21">21</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_22">22</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_23">23</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_24">24</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_25">25</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_26">26</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_27">27</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_28">28</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_29">29</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_30">30</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_31">31</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_32">32</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_33">33</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="http://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="http://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_34">34</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_35">35</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_36">36</a>,<a class="bk_pop" href="#CDR0000719335_rl_357_37">37</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_37">37</a>-<a class="bk_pop" href="#CDR0000719335_rl_357_39">39</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_36">36</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_40">40</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_41">41</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. 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[<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_34">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="http://www.nap.edu/openbook.php?record_id=5776&page=R1" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">available online</a>. Last accessed April 19, 2016. [<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_35">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_36">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_37">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_38">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_39">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_40">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_41">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 <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045113/" class="def">Selenium</a> and Vitamin E Cancer <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000439419/" class="def">Prevention</a> 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 selenium 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 supplementation 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 (ABCA1) 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></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_12">12</a>]</p><p id="CDR0000719335__345">Although not primarily designed for this purpose, the Alpha-Tocopherol, <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045328/" class="def">Beta Carotene</a> Cancer Prevention (ATBC) Study has been a resource for researchers investigating prostate cancer and vitamin E.[<a class="bk_pop" href="#CDR0000719335_rl_328_13">13</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_14">14</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 <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000045916/" class="def">supplementation</a> on prostate cancer risk.[<a class="bk_pop" href="#CDR0000719335_rl_328_15">15</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_16">16</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 <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046057/" class="def">Retinol</a>
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<a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000346517/" class="def">Efficacy</a> 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 <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000046053/" class="def">aggressive</a> 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_17">17</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_13">13</a>,<a class="bk_pop" href="#CDR0000719335_rl_328_18">18</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_19">19</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_19">19</a>]</p><p id="CDR0000719335__349">Initial results of SELECT were published in 2009. There were no <a href="/books/n/pdqcis/glossary/def-item/glossary_CDR0000044167/" class="def">statistically significant</a> 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_20">20</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_21">21</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_22">22</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_23">23</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_24">24</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_25">25</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="http://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="http://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_26">26</a>]</p><p id="CDR0000719335__354">In the Physicians’ Health Study II, there were no significant 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_12">12</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_13">13</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_20">20</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_21">21</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">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_13">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_14">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_15">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_16">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_17">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_18">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_19">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_20">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_21">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_22">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_23">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_24">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_25">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_26">Select Committee on GRAS Substances (SCOGS) Opinion: alpha-Tocopherols. Silver Spring, Md: Food and Drug Administration, 2013. <a href="http://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 19, 2016.</div></li></ol></div></div><div id="CDR0000719335__485"><h2 id="_CDR0000719335__485_">Multicomponent Therapies</h2><div id="CDR0000719335__486"><h3>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 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>] The food supplement 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 supplement 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__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_2">2</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_3">3</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_4">4</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_5">5</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_3">3</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_6">6</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_7">7</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_8">8</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_9">9</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_10">10</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 <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) 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_11">11</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_12">12</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_12">12</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">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_3">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_4">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_5">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_6">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_7">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_8">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_9">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_10">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_11">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_12">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.</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 (04/19/2016)</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__601"><b><a href="#CDR0000719335__174">Green Tea</a></b></p><p id="CDR0000719335__602">This section was comprehensively reviewed.</p><p id="CDR0000719335__603"><b><a href="#CDR0000719335__162">Pomegranate</a></b></p><p id="CDR0000719335__604">Added <a href="/books/NBK83261.6/#CDR0000719335__81">text</a> to state that a phase III placebo-controlled trial of pomegranate juice and extract did not show a significant increase in prostate-specific antigen (PSA) doubling time (PSADT).</p><p id="CDR0000719335__605">Added <a href="#CDR0000719335__253">text</a> to state that a phase III placebo-controlled trial of 183 patients who were randomly assigned to the pomegranate juice, pomegranate extract, or placebo did not significantly prolong PSADT in prostate cancer patients with rising PSA after primary therapy; some data from this study suggested that a subgroup analysis should be done to further investigate a potential unique sensitivity (cited Pantuck et al. as reference 20).</p><p id="CDR0000719335__586"><b><a href="#CDR0000719335__357">Vitamin D</a></b></p><p id="CDR0000719335__606">Revised <a href="#CDR0000719335__554">text</a> to state that administration of calcitriol was discontinued until hypercalcemia resolved; supplementation was restarted after two weeks.</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="http://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="http://www.cancer.gov/about-cancer/treatment/cam/hp/prostate-supplements-pdq" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">http://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="http://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="http://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="http://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="http://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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<div xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Views</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="PDF_download" 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/NBK83261.6/?report=reader">PubReader</a></li><li><a href="/books/NBK83261.6/?report=printable">Print View</a></li><li><a data-jig="ncbidialog" href="#_ncbi_dlg_citbx_NBK83261" data-jigconfig="width:400,modal:true">Cite this Page</a><div id="_ncbi_dlg_citbx_NBK83261" style="display:none" title="Cite this Page"><div class="bk_tt">PDQ Integrative, Alternative, and Complementary Therapies Editorial Board. 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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$=inpage&link_id=inpage">Changes to This Summary (04/19/2016)</a></li><li><a href="#CDR0000719335__AboutThis_1" ref="log$=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. 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