CHEMOPREVENTIVE ACTIVITY OF CELECOXIB, A SPECIFIC CYCLOOXYGENASE-2 INHIBITOR, AGAINST COLON CARCINOGENESIS

Epidemiological and laboratory studies suggest that nonsteroidal antii nflammatory drugs reduce the risk of colon cancer and that the inhibit ion of colon carcinogenesis is mediated through modulation of prostagl andin production by cyclooxygenase (COX) isozymes (COX-1 and -2). Over expression of COX-2 has been observed in colon tumors; therefore, spec ific inhibitors of COX-2 activity could potentially serve as chemoprev entive agents. Our recent study indicated that celecoxib (SC-58635), a specific COX-2 inhibitor, suppressed colonic aberrant crypt foci form ation induced by azoxymethane in rats and led us to investigate more s pecifically the chemopreventive potential of this compound using colon tumors as end points. Five-week-old male F344 rats were fed the contr ol diet (modified AIN-76A) or an experimental diet containing 1500 ppm celecoxib. Two weeks later, all animals except those in the saline-tr eated groups received s.c. injections of azoxymethane (15 mg/kg of bod y weight) once weekly for 2 weeks. All groups were kept on their regim en until the experiment was terminated, 50 weeks after carcinogen trea tment, Colon tumors were evaluated histopathologically. Remarkably, di etary administration of celecoxib inhibited both incidence and multipl icity of colon tumors by about 93 and 97%, respectively. It also suppr essed the overall colon tumor burden by more than 87%, The degree of t umor inhibition was more pronounced with celecoxib than it was,vith pr eviously evaluated nonsteroidal anti-inflammatory drugs. The results o f this study provide evidence, for the first time, that a specific COX -2 inhibitor, celecoxib, possesses strong chemopreventive activity aga inst colon carcinogenesis.