In this project studies will be carried out to assess the effect of calcium, a natural constituent of food, on the hyperproliferation and impaired maturation of colonic epithelial cells occurring in the mucosa of individuals with increased susceptibility to colon cancer. Measurements of cell proliferation and differentiation will serve as a rapid assay system to evaluate the utility of oral supplementary calcium in inducing repopulation of the colonic mucosa with normal epithelial cells. Recent findings in rodents have indicated that free unesterified fatty acids and free unconjugated bile acids induce damage of colonic epithelial cells, and that this toxicity can be neutralized by a relatively modest increase in calcium availability in the colon. We have now shown in humans that supplementary dietary calcium inhibits a hyperproliferative response of colonic epithelium occurring in individuals at increased risk for colon cancer. The studies proposed in this application are designed to test the effect of dietary calcium supplementation in a randomized controlled study in individuals at increased risk for colon cancer. In this disease, several subgroups will be examined that have previously been identified with increased susceptibility to colon cancer; the diseases are also characterized by increased proliferative activity of the colonic epithelial cells, previously determined by tritiated thymidine microautoradiography of rectal giopsies. Reduction of the elevated colonic epithelial cell profiles in individuals with increased susceptibility to colon cancer, represents a short-term human assay system, to further test the use of dietary calcium in reducing colon cancer risk in individuals with known increased susceptibility. Using the proposed methods of measuring indices both of cell proliferation and differentiation, reliable measurements can be made and translated into realistic assessments of risk reduction, based on the degree of modification of proliferative indices to those of the more quiescent profiles of low risk population groups previously studied.
