Cancer Epidemiology Biomarkers & Prevention, Vol 5, Issue 5 355-360, Copyright © 1996 by American Association for Cancer Research

ARTICLES

Aberrant crypts as a biomarker for colon cancer: evaluation of potential chemopreventive agents in the rat

MJ Wargovich, CD Chen, A Jimenez, VE Steele, M Velasco, LC Stephens, R Price, K Gray and GJ Kelloff
Department of Gastrointestinal Medical Onclolgy and Digestive Diseases, The University of Texas M.D. Anderson Cancer Center, Houston, USA.

We assessed the effects of 41 potential chemopreventive agents in the F344 rat using the inhibition of carcinogen-induced aberrant crypt foci (ACF) in the colon as the measure of efficacy. ACF were induced by the carcinogen azoxymethane in F344 rats by two sequential weekly injections at a dose of 15 mg/kg. Two weeks after the last azoxymethane injection, animals were evaluated for the number of aberrant crypts detected in methylene blue-stained whole mounts of rat colon. The 41 agents were derived from a priority listing that was based on reports of chemopreventive activity in the literature and/or efficacy data from in vitro models of carcinogenesis. The list of agents included representative examples of phytochemicals, vitamins, minerals, inhibitors of proliferation, inducers of Phase 1 and Phase 2 metabolism systems, nonsteroidal anti-inflammatory agents, and differentiation agents. Eighteen agents were positive in the assay, significantly reducing the incidence of ACF at least in one of two doses tested. As a chemical class, the nonsteroidal anti-inflammatory drugs, which included ibuprofen, ketoprofen, piroxicam, and indomethacin, were most active; other less potent agents were arginine, butylated hydroxyanisole, curcumin, diallyl sulfide, difluoromethylornithine, 18 beta-glycyrrhetinic acid, indole-3-carbinol, oltipraz, purpurin, rutin, and the sodium salts of butyrate, selenite, and thiosulfate. Twenty-three agents did not inhibit ACF; included among these were several agents that promoted the development of ACF at one or both doses tested: benzyl isothiocyanate,calcium glucarate, catechin, dihydroepiandosterone, fluocinolone acetonide,folic acid, levamisole, 2-mercaptoethanesulfonic acid, nordihydroguiaretic acid, potassium glucarate, propyl gallate, beta-sitosterol, sodium cromolyn, sodium molybdate, and sulfasalazine. The aberrant crypt assay demonstrates reasonable specificity and sensitivity in predicting which agents are likely to prevent colon cancer.

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