The general problem to be studied in this program is cancer chemoprevention. The specific focus of our work will be the chemoprevention of colorectal cancers, which are the second leading cause of cancer deaths in the United States of America. The long term objective of this program is to identify strategies of colon cancer chemoprevention that will reduce the incidence of, and/or the mortality due to, colon cancer. Our general approach will be to further define the mechanisms of colon carcinogenesis and identify methods that will inhibit this process. The overall hypothesis to be tested in this program is that colon carcinogenesis in humans is associated with a decrease in either the basal rate of inducibility of apoptosis in colonic mucosal cells. We will also test the related hypothesis that certain cancer chemopreventive agents inhibit colon carcinogenesis by stimulating apoptosis in neoplastic colonic tissues. This basic science research program is intended to complement existing clinical cancer chemoprevention trials ongoing at the Arizona Cancer Center and collaborative studies involving the University of California- Irvine and is intended to help our group answer critical questions relevant to future colon cancer chemoprevention trials. The unifying themes of this proposed program grant are colon carcinogenesis and colon cancer chemoprevention and the specific focus of the program will be the process of apoptosis. The objectives of the program will be to determine if a) apoptosis plays a role in colon polyp formation and subsequent colon cancer development, and b) potential chemopreventive strategies work by promoting apoptosis in addition to their effects on cell proliferation. Within this context, we intend to determine the roles of dietary and cellular factors in the occurrence of apoptosis in normal and neoplastic colonic tissues. In the course of these proposed studies, we plan to use a variety of cell culture models and tissues from both experimental animal models of colon carcinogenesis and biopsies from human patients participating in ongoing cancer chemoprevention trials. The program application includes 4 independent, but interrelated, research projects supported by 3 scientific cores.
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