CHEMOPREVENTION OF AZOXYMETHANE-INDUCED COLONIC CARCINOGENESIS BY SUPPLEMENTAL DIETARY URSODEOXYCHOLIC ACID

The present studies were conducted at the Universities of Chicago and Arizona to examine and compare the effects of supplemental dietary urs odeoxycholic acid to cholic acid, a known tumor promoter, and to pirox icam, a known chemopreventive agent, in the azoxymethane (AOM) model o f experimental colonic carcinogenesis. Male Fischer 344 rats were util ized in these experiments. Ah animals were fed a basaI diet (AIN-76) s upplemented with 0.2% or 0.4% cholic acid, 0.2% or 0.4% ursodeoxycholi c acid, 0.2% ursodeoxycholic acid plus 0.2% cholic acid, or 75 ppm pir oxicam. Rats were given s.c. injections once a week for 2 weeks with A OM (15 mg/kg body wt/week) or vehicle (saline) after being fed their r espective diets for 2 weeks. The rats in each group were then maintain ed on their respective diets for approximately 28 weeks; after sacrifi ce, their colons were removed and examined macroscopically and microsc opically for the presence of tumors. The results of these studies demo nstrated that none of the control rats fed the various diets injected with AOM-vehicle developed tumors. In groups receiving AOM, the additi on of cholic acid (0.4%) caused a significant increase in the incidenc e of tumors. In contrast, the addition of 0.2% ursodeoxycholic acid di d not promote AOM-induced colonic tumors, and when it was added to a p romoting dose of cholic acid (0.2%), 0.2% ursodeoxycholic acid prevent ed enhancement of tumor promotion. At higher doses (0.4%), supplementa l dietary ursodeoxycholic acid significantly reduced the incidence of colon tumors and cancers. Moreover, the tumor suppressive effects of 0 .4% ursodeoxycholic acid exceeded that of dietary piroxicam. Our resul ts further emphasize the important role of bile salts in modulating co lonic tumor development. These studies also demonstrate for the first time that supplemental dietary ursodeoxycholic acid is a chemopreventi ve agent in the AOM model of experimental colonic carcinogenesis.