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To identify the efficacy of chemopreventive agents and their effect on progressive stages of colonic preneoplasia and tumor evolution, new preclinical models have recently been developed. Some of these models have targeted mutations that modify the incidence and progression of neoplastic lesions. In one model of inherited predisposition to colon cancer mice carrying a truncated Apc allele with a nonsense mutation in econ 15 (Apc1638 mice) develop multiple gastrointestinal lesions, including adenomas and carcinomas, focal areas of high-grade dysplasia (fad) and polypoid hyperplasias with fads. The incidence of inherited intestinal neoplasms including colonic significantly increased in Apc1638 mice on a Western-style diet with higher fat content and lower calcium and vitamin D compared to AIN-76A diet. Min mice with an Apc mutation had a reduced incidence of intestinal tumors after Sulindac administration. Mice carrying a targeted mutation in the gene Mcc (mutated in colorectal cancer) develop multiple types of neoplasms including adenocarcinomas, focal areas of gastrointestinal dysplasia, papillomas of the forestomach and tumors in other organs including lung, liver and lymphoid tissue. feeding a Western-style diet to Mcc mutant mice also significantly increased gastrointestinal lesions. In normal mice a Western-style diet also induced whole-crypt colonic dysplasias without any chemical carcinogen. Western-style diets have now induced epithelial cell hypoproliferation in other organs including mammary gland, pancreas and prostate. These findings are leading to the development of new preclinical rodent models to aid the analysis of genetic and environmental factors leading to neoplasia, and are assisting clinical studies to evaluate the chemopreventive efficacy of specific nutrients and pharmacological agents. Human studies of chemopreventive regimens are underway to evaluate efficacy in colon, breast, esophagus, stomach, cervix, liver, lung and other organs, and these clinical trials are underway in many countries worldwide.
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