GENE MUTATIONS AND APOPTOSIS IN CANCER CHEMOPREVENTION

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Clonic epithelium survives in a balanced state of continuous proliferation coupled with colonocyte death and/or shedding. Recent evidence now demonstrates that oncogenes and tumor suppressor genes play important roles in a unique mode of cell death, termed apoptosis. The central hypothesis to be tested in this proposal is that specific gene mutations, or alterations in specific gene expression, affect apoptosis as well as cell proliferation in colonic mucosa. Related hypotheses are that specific gene mutations or alterations in specific gene expression may affect apoptosis induced by dietary factors, such as bile acids, and certain cancer chemopreventive agents may work via mechanisms that induce apoptosis selectively in genomically altered cells. Proposed studies will focus on alterations in the oncogenes Ki-ras and bcl-2 and the tumor suppressor genes p53 and APC and the chemopreventive agents DFMO, ursodeoxycholate and the NSAIDs Ibuprofen and sulinidac sulfone. In order to test the hypotheses stated above, the Specific Aims of this proposal are as follows. "Determine the consequences of specific gene alterations on proliferation and apoptosis in apparently normal and neoplastic colonic tissues obtained from rodent models of colon carcinogenesis. Measure the effects of cancer chemopreventive agents on proliferation, apoptosis and specific gene mutations in normal and neoplastic colorectal tissue from animal models and human selected human populations. Determine if specific gene mutations render normal or neoplastic colon- derived cells more susceptible to cancer chemopreventive agent-induced growth inhibition or apoptosis. Determine if specific gene mutations influence apoptosis induced by bile acids in normal and neoplastic human colon-derived cells and colonic tissues derived from rodents and humans. The long term goal of this proposal is to define the mechanisms by which specific colon cancer chemopreventive agents exert their anti-carcinogenic effects in order to define optimally effective applications of individual, or combinations of multiple, agents. Results from this work should further establish the rationale for some colon cancer chemopreventive agents, and may define new and more effective strategies to treat or prevent colon cancer.