INHIBITORY EFFECT OF ASPIRIN ON AZOXYMETHANE-INDUCED COLON CARCINOGENESIS IN F344 RATS

Epidemiologic studies suggest that sustained use of aspirin may reduce the risk of development of and mortality due to colon cancer. Previou s preclinical studies have shown that several non-steroidal anti-infla mmatory drugs act as potential chemopreventive agents in experimentall y induced colon cancer models. The present study was designed to inves tigate the chemopreventive effect of 40 and 80% maximum tolerated dose (MTD) levels of aspirin administered in the diet on azoxymethane (AOM )-induced colon carcinogenesis in male F344 rats. The MTD of aspirin a s determined in male F344 rats was 500 p.p.m. Beginning at 5 weeks of age, all animals were randomly divided into various experimental group s (48 rats/group) and fed one of the semipurified diets containing 0, 200 p.p.m. (40% MTD), or 400 ppm (80% MTD) of aspirin. Two weeks later , all animals (36 rats/group) except the vehicle-treated groups (12 ra ts/group) were administered s.c. injections of AOM at a dose level of 15 mg/kg body wt, once weekly for 2 weeks. All animals were continued on their respective dietary regimen for additional 52 weeks and necrop sied. Histopathologic evaluation of colon tumors was performed by rout ine procedures. Basal levels and ex vivo production of colonic mucosal and tumor prostaglandin E2 (PGE2) were measured in all groups. The re sults indicate that daily oral administration of 200 and 400 p.p.m. as pirin significantly inhibited the incidence (% animals with tumors) an d multiplicity (tumors/animal) of invasive adenocarcinomas of the colo n as well as the size of adenocarcinomas. Colonic mucosal and tumor PG E2 levels (basal and ex vivo production) were significantly reduced in animals administered 200 and 400 p.p.m. aspirin. The results of this study support the epidemiologic evidence that ingestion of aspirin inh ibits colon carcinogenesis. Although the precise mechanisms of aspirin -induced colon tumor inhibition remain to be determined, it is likely that the effect may be mediated through the modulation of prostaglandi n synthesis.