Use of azoxymethane-induced foci of aberrant crypts in rat colon to identify potential cancer chemopreventive agents

Foci of aberrant and/or hexosaminidase-negative crypts in ratcolon are putative precancerous lesions that have been proposedas biomarkers for Short-term bioassays for chemical carcinogensand chemopreventive agents. The ability of a substance to reducethe yield of azoxymethane (AOM)- induced foci in the colon ofmale Fischer 344 rats, was evaluated as a screening assay forchemopreventive agents. Twenty-eight test agents were administeredcontinuously in the diet from the start of the experiments untilthe animals were killed 35 days later. AOM was s.c. administeredeither as 15 mg/kg body wt on days 7 and 14 or as 30 mg/kg bodywt on day 7 of the experiment. Foci of aberrant crypts wereevaluated in whole mounts of methylene blue-stained colons.AOM induced twice as many foci when administered between 8.40and 11.00 a.m. than between 2.45 and 5.55 p.m. Calcium saltsof carbonate, chloride and glucarate decreased the yield ofAOM-induced foci while the acidic salts of lactate and phosphatedid not inhibit the formation of foci. Dimethyl fumarate, fumaricacid, genistein, piroxicam, simethicone, sodium suramin andsulindac reduced the yield of AOM induced foci of aberrant cryptswith genistein being the most potent. Only piroxicam of thisgroup has previously been shown to inhibit colon cancer, whilethe rest have yet to be evaluated. Ibuprofen did not inhibitthe formation of foci, although it has been reported to inhibitAOM-induced colon cancer in rats. Piroxicam and sulindac appearedto reduce preferentially hexosaminidase-negative foci of aberrantcrypts, compared with those of apparently normal morphology.The AOM-induced foci of aberrant crypts assay appears suitablefor screening chemicals for chemopreventive action.