Colon Cancer Chemoprevention

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DESCRIPTION (provided by applicant): We have previously demonstrated that supplemental dietary Ursodeoxycholic Acid (UDCA) inhibited the development of azoxymethane-induced rat colonic tumors. To examine the mechanisms by which UDCA causes anticarcinogenic effects, studies in this proposal demonstrated that UDCA increased RasGAP activity and generated caspase-3 dependent RasGAP -N and -C terminal fragments. The important goal of this application is to determine whether RasGAP C-terminal fragment has a role in the inhibition of colon cancer. In cell culture studies we have demonstrated that RasGAP C-terminal fragment sensitizes colon cancer cells towards UDCA-induced apoptosis. To study tumor suppression by RasGAP C-terminal fragments, in vivo, we will utilize nude mouse model. This will be the first attempt to evaluate the anti-cancer activity of RasGAP C-terminal fragment in colon cancer. Colon cancer cells over-expressing RasGAP C-fragment protein will be injected into mice and tumor growth characteristics will be observed in the presence of UDCA. Further, we have also utilized an innovative technology in isolating RasGAP C-fragment protein attached to a HIV peptide, which permits its transport across cell membranes. To assess the therapeutic benefit, this protein will be injected directly in the tumor. Our rationale for these studies is that development of scientifically based evidence to support a preventive and therapeutic benefit of RasGAP C-terminal fragment would provide a foundation for human studies to test potential benefits in cancer patients and high risk individuals. It is hoped that the information gained by this proposal can be exploited and applied towards the design of a more effective inhibitor for colon cancer prevention and therapy.