Efficacy of potential chemopreventive agents on rat colon aberrant crypt formation and progression

We assessed the effects of 78 potential chemopreventive agents in the F344 rat using two assays in which the inhibition of carcinogen-induced aberrant crypt foci (ACF) in the colon was the measure of efficacy. In both assays ACF were induced by the carcinogen azoxymethane (AOM) in F344 rats by two s equential weekly injections at a dose of 15 mg/kg. Two weeks after the last AOM injection, animals were evaluated for the number of aberrant crypts de tected in methylene blue stained whole mounts of rat colon. In the initiati on phase protocol agents were given during the period of AOM administration , whereas in the post-initiation assay the chemopreventive agent was introd uced during the last 4 weeks of an 8 week assay, a time when ACF had progre ssed to multiple crypt clusters. The agents were derived from a priority li sting based on reports of chemopreventive activity in the literature and/ o r efficacy data from in vitro models of carcinogenesis. During the initiati on phase carboxyl amidoimidazole, p-chlorphenylacetate, chlorpheniramine ma leate, D609, diclofenac, etoperidone, eicosatetraynoic acid, farnesol, feru lic acid, lycopene, meclizine, methionine, phenylhexylisothiocyanate, pheny lbutyrate, piroxicam, 9-cis-retinoic acid, S-allylcysteine, taurine, tetrac ycline and verapamil were strong inhibitors of ACF. During the post-initiat ion phase aspirin, calcium glucarate, ketoprofen, piroxicam, 9-cis-retinoic acid, retinol and rutin inhibited the outgrowth of ACF into multiple crypt clusters. Based on these data, certain phytochemicals, antihistamines, non -steroidal antiinflammatory drugs and retinoids show unique preclinical pro mise for chemoprevention of colon cancer, with the latter two drug classes particularly effective in the post-initiation phase of carcinogenesis.