Utility of Apc-mutant rats with a colitis-associated colon carcinogenesis model for chemoprevention studies.

Abstract

Establishment of an efficient rat model for colitis-associated colon carcinogenesis is critical for evaluation of the potency of cancer-preventive agents on carcinogenesis. In the present study, we examined whether the Kyoto Apc Delta (KAD) rat, a novel adenomatous polyposis coli mutant rat strain, is useful for detection of potential chemopreventive agents when this rat is used for azoxymethane (AOM) plus dextran sulfate sodium (DSS)-induced colitis-associated colon carcinogenesis with well-known cancer chemopreventive agents, such as celecoxib and (-)-epigallocatechin-3-gallate (EGCG). Male KAD rats were administered a single subcutaneous injection of AOM (20 mg/kg body weight) at 5 weeks of age and 2% DSS in their drinking water for subsequent 7 days starting at 1 week after the AOM injection. The rats were also treated with either celecoxib (500 ppm in the diet) or EGCG (0.1% in their drinking water), and the effects of these agents on the development of colonic tumors were examined. At sacrifice (19 weeks of age), treatment with both celecoxib (74% inhibition, P<0.01) and EGCG (71% inhibition, P<0.05) significantly inhibited the development of colitis-associated colon tumors. Serum levels of oxidative stress products, which were increased by AOM/DSS treatment, were decreased by celecoxib and EGCG. Administration of these agents moreover lowered the serum levels of inflammatory mediators, including tumor necrosis factor-α, interleukin-6, cyclooxygenase-2, and inducible nitric oxide synthase, in the AOM/DSS-treated KAD rats. These findings suggest that this AOM/DSS-induced colon carcinogenesis model using KAD rats may be useful for evaluation of the efficacy of cancer-preventive agents.