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. 2004 Oct;127(4):1030-7.
doi: 10.1053/j.gastro.2004.07.059.

Suppression of Peutz-Jeghers polyposis by inhibition of cyclooxygenase-2

Lina Udd  1 , Pekka Katajisto, Derrick J Rossi, Anna Lepistö, Anna-Maria Lahesmaa, Antti Ylikorkala, Heikki J Järvinen, Ari P Ristimäki, Tomi P Mäkelä
Affiliations

Suppression of Peutz-Jeghers polyposis by inhibition of cyclooxygenase-2

Lina Udd et al. Gastroenterology. 2004 Oct.

Abstract

Background & aims: Peutz-Jeghers syndrome (PJS) is typically manifested as severe gastrointestinal polyposis. Polyps in PJS patients and in Lkb1(+/-) mice that model PJS polyposis are frequently characterized by elevated cyclooxygenase-2 (COX-2). This study was designed to determine whether COX-2 inhibition would reduce tumor burden in Lkb1(+/-) mice or Peutz-Jeghers patients.

Methods: Genetic interactions between Cox-2 and Lkb1 in polyp formation were analyzed in mice with combined deficiencies in these genes. Pharmacologic inhibition of COX-2 was achieved by supplementing the diet of Lkb1(+/-) mice with 1500 ppm celecoxib between 3.5-10 and 6.5-10 months. In PJS patients, COX-2 was inhibited with a daily dose of 2 x 200 mg celecoxib for 6 months.

Results: Total polyp burden in Lkb1(+/-) mice was significantly reduced in a Cox-2(+/-) (53%) and in a Cox-2(-/-) (54%) background. Celecoxib treatment initiating before polyposis (3.5-10 months) led to a dramatic reduction in tumor burden (86%) and was associated with decreased vascularity of the polyps. Late treatment (6.5-10 months) also led to a significant reduction in large polyps. In a pilot clinical study, a subset of PJS patients (2/6) responded favorably to celecoxib with reduced gastric polyposis.

Conclusions: These data establish a role for COX-2 in promoting Peutz-Jeghers polyposis and suggest that COX-2 chemoprevention may prove beneficial in the treatment of PJS.

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