Inhibition of AOM-Induced Colorectal Cancer by CP-31398, a TP53 modulator, Alone or in Combination with Low Doses of Celecoxib in Male F344 Rats

Tumor suppressor p53 plays a major role in colorectal cancer development. The present study explores the effects of p53 modulating agent CP-31398 alone and combined with celecoxib on azoxymethane (AOM)-induced aberrant crypt foci (ACF) and colon adenocarcinomas in F344 rats. Maximum tolerated doses were 400 and 3000 ppm for CP-31398 and celecoxib, respectively. ACF and tumor efficacy endpoints were carried out on AOM-treated seven week old rats (48/group) fed the control AIN-76A diet. Two weeks after carcinogen treatment, rats were fed the diets containing 0, 150, 300 ppm of CP-31398, or 300 ppm of celecoxib, or 150 ppm CP-31398 plus 300 ppm celecoxib. ACF were determined at 8 weeks and colon adenocarcinomas 48 weeks after AOM treatment. Dietary CP-31398 was shown to suppress mean colonic total ACF by 43% and multicrypt ACF by 63%; dietary CP-31398 at 150 and 300 ppm suppressed adenocarcinoma incidence by 30.4% (p