CHEMOPREVENTION BY PRAVASTATIN, A 3-HYDROXY-3-METHYLGLUTARYL-COENZYME-A REDUCTASE INHIBITOR, OF N-METHYL-N-NITROSOUREA-INDUCED COLON CARCINOGENESIS IN F344 RATS

A potential chemopreventive action of pravastatin (Pr), a 3-hydroxy-3- methylglutaryl-coenzyme A reductase inhibitor, on colon carcinogenesis was evaluated in F344 rats. All rats at 7 weeks of age received an in trarectal dose of 2 mg of N-methyl-N-nitrosourea 3 times weekly for 2 weeks in experiment I (2 groups of 16 rats each), and for 3 weeks in e xperiment II (4 groups of 30 rats each). They were given drinking wate r containing 0 ppm (control) or 200 ppm Pr during weeks 1 to 40 in exp eriment I, and containing 0 ppm (control), 25 ppm, 5 ppm and 1 ppm Pr during weeks 4 to 40 in experiment II. The body weight gains, and food and water intakes were similar in all the groups. The incidence of co lon carcinomas at termination of the experiment at week 40 was not dif ferent in the 200 ppm Pr and control groups in experiment I (63% vs. 6 9%), while it was significantly lower in the 25 ppm and 5 ppm groups, but not in the 1 ppm Pr group, compared with the control group in expe riment II (50%, 48%, and 77% vs, 80%). This inhibitory effect of Pr ag ainst colon carcinogenesis was not related to the cholesterol-lowering effect of this agent. We postulate that Pr inhibits the promotion sta ge of colon carcinogenesis, perhaps through modulation of cholesterol synthesis in situ in the colonic mucosa, thereby suppressing farnesyl isoprenylation of growth-regulating proteins such as p21 ras.