CYCLOOXYGENASE-2 OVEREXPRESSION AND TUMOR-FORMATION ARE BLOCKED BY SULINDAC IN A MURINE MODEL OF FAMILIAL ADENOMATOUS POLYPOSIS

Inducible cyclooxygenase (Cox-2), also known as prostaglandin H syntha se 2 (PGH-2) is a key enzyme in the formation of prostaglandins and th romboxanes, Cox-2 is the product of an immediate-early gene that is ex pressed in response to growth factors, tumor promoters, or cytokines. Overexpression of Cox-2 is associated with both human colon cancers an d suppression of apoptosis in cultured epithelial cells, an activity t hat is reversed by the nonsteroidal anti-inflammatory drug, sulindac s ulfide, To address the relationship between Cox-2, apoptosis, and tumo r development in vivo, we studied C57BL/6J-Min/+(Min) mice, a strain c ontaining a fully penetrant dominant mutation in the Ape gene, leading to the development of gastrointestinal adenomas by 110 days of age, M in mice were fed AIN-76A chow diet and given sulindac (0.5 +/- 0.1 mg/ day) in drinking water, Control Min mice and homozygous C57BL/6J-+/+ n ormal littermates lacking the Ape mutation (+/+) were fed AIN-76A diet and given tap water to drink, At 110 days of age, all mice were sacri ficed, and their intestinal tracts were examined, Control Min mice had 11.9 +/- 7.8 tumors per mouse compared to 0.1 +/- 0.1 tumors for suli ndactreated Min mice, As expected, +/+ littermates had no macroscopic tumors. Examination of histologically normal-appearing small bowel fro m Min animals revealed increased amounts of Cox-2 and prostaglandin E( 2) compared to +/+ littermates, Using two different in situ techniques , terminal transferase-mediated dUTP nick end labeling and a direct im munoperoxidase method, Min animals also demonstrated a 27-47% decrease in enterocyte apoptosis compared to +/+ animals, Treatment with sulin dac not only inhibited tumor formation but decreased small bowel Cox-2 and prostaglandin E, to baseline and restored normal levels of apopto sis, These data suggest that overexpression of Cox-2 is associated wit h tumorigenesis in the gastrointestinal epithelium, and that both are inhibited by sulindac administration.