DO NSAIDS EXERT THEIR COLON-CANCER CHEMOPREVENTION ACTIVITIES THROUGHTHE INHIBITION OF MUCOSAL PROSTAGLANDIN SYNTHETASE

Nonsteroidal antiinflammatory drugs (NSAIDs) have considerable potenti al as chemopreventive agents for colorectal cancer. Recent case-contro l drug surveillance and large cohort studies found that patients with regular aspirin use had a reduced incidence of colorectal cancer and/o r decreased death rate from this disease. Several different NSAIDs red uce formation of both colon adenomatous polyps (the precursor lesion o f colon cancer) and cancers in experimental. animals given known carci nogens. Perhaps most convincing are reports that the NSAID sulindac pr omotes regression and inhibits recurrence of adenomatous colon polyps in patients with adenomatous polyposis coli. The best characterized ph armacologic effect of the NSAIDs is their reduction of prostaglandin s ynthesis by inhibiting prostaglandin synthetase PGE(2), which catalyze s the formation of prostaglandin precursors from arachidonic acid. Sev eral Lines of evidence are contrary to the concept that inhibition of prostaglandin synthesis is central to the NSAIDs' chemopreventive effe cts. Relatively high levels of prostaglandins have been reported to in hibit tumor cell growth both in vivo and in vitro, and to inhibit diff erentiation in some tumor cell lines. We evaluated comparative chemopr eventive effects on colon tumor formation in an azoxymethane (AOM)-ind uced colon carcinogenesis rat model using the NSAIDs piroxicam, sulind ac, and sulindac sulfone, a metabolite of sulindac which lacks the ant i-prostaglandin synthetase activity typically associated with NSAID-in duced gastrointestinal toxicities. The results demonstrate that sulind ac sulfone, a compound lacking anti-prostaglandin synthetase activity, inhibits AOM-induced colon cancer in rats. Substantial dose-dependent reductions in both tumor burden and tumor multiplicity were observed in the sulindac sulfone-treated animals. Although both piroxicam and s ulindac significantly reduced rat colonic mucosal PGE(2) levels to les s than 50% of their AOM control value, even the highest dietary concen tration of sulindac sulfone had no statistically significant effect on mucosal PGE(2) concentrations. These results suggest that NSAIDs do n ot exert their colon cancer chemoprevention activities through the inh ibition of mucosal prostaglandin synthetase. (C) 1995 Wiley-Liss, Inc.