CHEMOPREVENTION OF COLON CARCINOGENESIS BY SULINDAC, A NONSTEROIDAL ANTIINFLAMMATORY AGENT

Abstract

Epidemiological and laboratory animal model studies have suggested that nonsteroidal anti-inflammatory drugs reduce the risk of development of colon cancer. The present study was designed to investigate the chemopreventive action of 160 and 320 ppm (equivalent to 40 and 80% maximum tolerated doses) sulindac, a nonsteroidal anti-inflammatory drug, fed during initiation and postinitiation stages and 320 ppm sulindac fed during promotion/progression stages of azoxymethane-induced colon carcinogenesis in male F344 rats. Also investigated was the modulating effect of this agent on the colonic mucosal and tumor phospholipase A(2), phosphatidylinositol-specific phospholipase C, lipoxygenase, and cyclooxygenase activities. At 5 weeks of age, groups of male F334 rats were fed control diet or diets containing 160 and 320 ppm of sulindac. At 7 weeks of age, all animals except those in the vehicle-treated groups were given two weekly s.c. injections of azoxymethane at a dose rate of 15 mg/kg body weight/week. Animals intended for tumor promotion/progression study were administered 320 ppm of sulindac in diet starting at 14 weeks after a second azoxymethane treatment. All animals continued on their respective dietary regimen until the termination of the experiment at 52 weeks after the carcinogen treatment. Colonic tumors were evaluated histopathologically. Colonic mucosa and tumors were analyzed for phospholipase A(2), phosphatidylinositol-specific phospholipase C, prostaglandin E2, cyclooxygenase, and lipoxygenase acti,ities. The levels of sulindac and its metabolites in stomach, cecal, and fecal contents and in serum were analyzed, The results indicate that dietary sulindac at 160 and 320 ppm levels inhibited the incidence of invasive and noninvasive adenocarcinomas of the colon (P < 0.01-0.001) as well as their multiplicity (P < 0.01-0.0001) in a dose-dependent manner. Also, feeding sulindac during promotion/progression stages significantly suppressed the incidence (P < 0.0001) and multiplicity (P < 0.0001) of colonic adenocarcinomas. Dietary sulindac also suppressed the colon tumor volume by >52-62% compared to the control diet. Dietary sulindac significantly decreased the activities of phosphatidy linositol-specific phospholipase C (32-51%) and levels of prostaglandin E(2) (>40% in the colonic mucosa and tumors, but it had no significant (P > 0.05) effect on phospholipase A(2) activity, The formation of cyclooxygenase metabolites, particularly prostaglandin E(2), prostaglandin F-2 alpha, prostaglandin D-2, 6-ketoprostaglandin F-1 alpha, and thromboxane B-2, and lipoxygenase metabolites such as 8(S)- and 12(S)-hydroxyeicosatetraenoic acids were significantly reduced in colonic mucosa and tumors of animals fed 320 ppm sulindac. Also, animals fed 320 ppm sulindac showed increased levels of microbial metabolites of sulindac in cecal and fecal contents and in serum as compared to those fed 160 ppm sulindac, Although the exact mechanism by which sulindac inhibits colon tumorigenesis remains to be elucidated, it is likely that its chemopreventive action, at least in part, mag be related to the modulation of arachidonic acid metabolism.