Chemoprevention of Arylamine-Induced Colorectal Aberrant Crypts

Abstract

Since recombinant human cyclooxygenase (COX) enzymes have been shown to activate environmental and dietary carcinogens implicated in human colorectal cancer etiology, we hypothesized that COX-2 inhibitors reduce arylamine-induced aberrant crypts (AC) and foci (ACF), preneoplastic lesions of colorectal cancer. Male weanling F344 inbred rats were fed modified AIN-76A control diet or the same diets supplemented with 320 ppm sulindac or 500, 1000, or 1500 ppm celecoxib. At 7 weeks of age, rats received a subcutaneous injection of 3,2′-dimethyl-4-aminobiphenyl (DMABP), an aryl-amine colon carcinogen, once weekly for two weeks. Ten weeks after the initial DMABP or vehicle treatment (at 17 weeks of age), rats were euthanized with CO2, and the entire colorectum was removed and scored for ACF and AC. ACF possessing one to five AC were identified in the colorectum of rats administered DMABP, whereas no AC/ACF were identified in vehicle-treated controls. Significant reductions (p < 0.001) in ACF and AC frequencies were observed in DMABP-treated rats supplemented with sulindac or celecoxib. Celecoxib reduced AC and ACF more than sulindac, but this difference was not significant (p > 0.05). Reductions in both AC and ACF were highest following treatment with 1000 ppm celecoxib. These results provide additional experimental support for the chemopreventive effects of COX inhibitors in arylamine-induced colorectal cancer.