The overall objective of this proposal is to determine the chemopreventive efficacy of a combination of lovastatin (3-hydroxy-3-methylglutaryl CoA reductase (HMG-R) inhibitor and celecoxib (COX-2-selective inhibitor) against colon cancer and to gain an understanding of the mechanism(s) of tumor inhibition by these agents. Colorectal cancer is one of the most common human malignancies in the United States, anticipated to account for 137,000 new cases and about 56,000 deaths in the year 2001. Developing chemopreventive agent(s) that aim to suppress tumor cell growth, but not normal cell growth, by targeting specific genes/factors that are responsible for tumor growth provides a rational approach. Our studies and those of others indicate that COX-2 and HMG-R activities were up-regulated several-fold in colon tumors compared to normal mucosa and, importantly, the metabolites/molecules derived from these enzymes play a pivotal role in modulation of apoptosis and proliferation. Recent evidence from clinical trials, and in vivo and in vitro laboratory studies suggest that application of a combination of HMG-R inhibitors (cholesterol-lowering drugs) and COX-inhibitors (nonsteroidal anti-inflammatory drugs) produces synergistic colon cancer-inhibiting effects. Thus, it is important to systematically develop HMG-R inhibitors and their combination with COX-2 inhibitors for colon cancer prevention and delineate the specific mechanisms that lead to modulation of apoptosis and proliferation by these agents. Specifically, we will examine 1) the chemopreventive efficacy of lovastatin on azoxymethane (AOM)-induced colon carcinogenesis in rats (maximum tolerated dose selection; dose-response effects; and effectiveness during promotion/progression stages, 2) study the synergistic effects of lovastatin and celecoxib on AOM-induced colon carcinogenesis and assess effectiveness of these agents in combination on the promotion/progression stages, and 3) elucidate mechanisms by determining the effect(s) of lovastatin with or without combination of celecoxib on HMG-CoA reductase, FPTase, GGPTase, p53, p21CIP/WAF1, caspase-3 &- 6, Bax, Bcl-2, Fas and lamin B, COX-2, PPAR-y, p53, and prostaglandins levels. Finally, we will study the effects of these agents on cell proliferation, and apoptosis during different stages of colon carcinogenesis.
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