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 exon 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-stlye 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.