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

Abstract

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 sequential 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 detected in methylene blue stained whole mounts of rat colon. In the initiation phase protocol agents were given during the period of AOM administration, whereas in the post-initiation assay the chemopreventive agent was introduced during the last 4 weeks of an 8 week assay, a time when ACF had progressed to multiple crypt clusters. The agents were derived from a priority listing based on reports of chemopreventive activity in the literature and/or efficacy data from in vitro models of carcinogenesis. During the initiation phase carboxyl amidoimidazole, p-chlorphenylacetate, chlorpheniramine maleate, D609, diclofenac, etoperidone, eicosatetraynoic acid, farnesol, ferulic acid, lycopene, meclizine, methionine, phenylhexylisothiocyanate, phenylbutyrate, piroxicam, 9-cis-retinoic acid, S-allylcysteine, taurine, tetracycline and verapamil were strong inhibitors of ACF. During the post-initiation 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 anti-inflammatory drugs and retinoids show unique preclinical promise for chemoprevention of colon cancer, with the latter two drug classes particularly effective in the post-initiation phase of carcinogenesis.

Deguelin suppresses the formation of carcinogen‐induced aberrant crypt foci in the colon of CF‐1 mice

“…14,19 Likewise, deguelin significantly decreased the number of ACF/colon during initiation by 50.9% (p Ͻ 0.05) and during promotion by 73.3% (p Ͻ 0.001) ( Table I). These results showed that the time of administration of either agent was not a significant (p Ͼ 0.05) factor.…”

“…12 As a result, numerous studies have used the ACF assay to assess the efficacy of chemopreventive compounds. [13][14][15][16] Another important biomarker in the field of colon carcinogenesis is hex, a lysosomal enzyme active in normal colonic crypts yet decreased in up to 95% of ACF. 17 Decreased hex activity has been demonstrated in crypts with aberrant morphology (i.e., ACF) as well as in those that appear to have normal morphology.…”

“…19 Consequently, many chemopreventive agents have been evaluated using ACF and hex activity as end points. [13][14][15][16] These include curcumin, 15 quercetin, 13 saponin 16 and phenethylisothiocyanate. 16 Piroxicam, an NSAID used for the treatment of inflammatory arthritis, has also received significant attention.…”

“…[13][14][15] For example, rotenone derived from Derris and Lonchocarpus species root has been evaluated for its potential anticancer properties. 21,22 In an experimental colon cancer model, Yoshitani et al 22 investigated the effect of rotenone on the development of AOM-induced colon tumorigenesis and found that dietary administration at a dose of 500 ppm significantly reduced the occurrence of ACF by 50% compared to control animals.…”

Epigenetic inactivation of calcium-sensing receptor in colorectal carcinogenesis

“…4,5 Calcium-sensing receptor (CASR) is a member of the G protein-coupled receptor family. Extracellular Ca 2 þ and CASR serve as a first messenger system in controlling biological function.…”