Metformin, an insulin-lowering agent, has been associated with decreased cancer risk in epidemiologic studies in diabetic patients. Short-term preclinical and clinical observations also supported inhibition of colonic precancerous lesions. However, recent meta-analysis studies show that metformin or related drugs may reduce risk of pancreatic and hepatocellular carcinoma but a non-significant inverse correlation with colon cancer risk. The present study explores a systematic analysis of chemopreventive efficacies of metformin on a well established model of colon carcinogenesis, using colonic preneoplastic lesions and adenocarcinomas as end points. Effect of dietary metformin (100 ppm, 400 ppm, 800 ppm to 1,600 ppm) on AOM-induced aberrant crypt foci (ACF) development; and a dietary metformin (500 ppm and 1,000 ppm) on AOM-induced colon adenocarcinoma was studied in F344 rats. ACF and tumor efficacy endpoints were carried out on AOM-treated 8-week-old rats (48 per group) fed the control AIN-76A diet. Either three days (ACF Study) or 4 weeks (adenocarcinoma study) after carcinogen treatment, rats were fed the diets containing different doses of metformin. ACF and colon adenocarcinomas were determined at 8 and 48 weeks after AOM-treatment, respectively. Dietary metformin at 100 and 400 ppm had no significant effect on the colonic ACF formation; whereas at higher doses a significant increase was observed in the total ACF (37%) and multicrypt ACF by 43%. In long term bioassay, dietary metformin at 500 and 1,000 ppm had no significant effect on adenocarcinoma incidence. With regard to colon adenocarcinoma multiplicity, metformin at both dose levels failed to provide any inhibitory effect, albeit, modest increase (∼20%) in adenocarcinoma multiplicity at high dose level was seen. Similarly, dietary metformin fail to show any inhibitory effect on colon tumor volume. Rats that were fed with metformin fail to show significant effects on markers of cell proliferation and apoptosis in colonic tumors. These observations show, for the first time, that metformin tested at different dose levels does not provide chemopreventive effects at the preneoplastic lesion stage or at adenocarcinoma stages in a well-established rat colon cancer model. Further studies are warranted to understand the discrepancies between preclinical models and more so in human clinical observations on the potential beneficial effects of metformin for colon cancer risk.

{This work is supported by NCI-N01 CN-53300}

Citation Information: Cancer Prev Res 2011;4(10 Suppl):B42.