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 synthase 2 (PGH-2) is a key Enzyme in the formation of prostaglandins and thromboxanes. COX-2 is the product of an immediate-early gene that is expressed in response to growth factors, tumor promoters, or cytokines. Overexpression of COX-2 is associated with both human colon cancers and suppression of Apoptosis in cultured epithelia] cells, an activity that is reversed by the nonsteroidal anti-inflammatory drug, sulindac sulfide. To address the relationship between COX-2, Apoptosis, and tumor development in vivo, we studied C57BL/6J-Min/+(Min) mice, a strain containing a fully penetrant dominant mutation in the APC gene, leading to the development of gastrointestinal adenomas by 110 days of age. Min 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-+/+ normal littermates lacking the APC mutation (+/+) were fed AIN-76A diet and given tap water to drink. At 110 days of age, all mice were sacrificed, 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 sulindac-treated Min mice. As expected, +/+ littermates had no macroscopic tumors. Examination of histologically normal-appearing small bowel from 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 immunoperoxidase method, Min Animals also demonstrated a 27-47% decrease in enterocyte Apoptosis compared to +/+ Animals. Treatment with sulindac not only inhibited tumor formation but decreased small bowel COX-2 and prostaglandin E(2) to baseline and restored normal levels of Apoptosis. These data suggest that overexpression of COX-2 is associated with tumorigenesis in the gastrointestinal epithelium, and that both are inhibited by sulindac administration.