(Applicant's Description) The overall goal of this Program Project Grant is to determine the molecular mechanisms involved in the chemoprevention of colorectal cancer by non- steroidal anti-inflammatory drugs (NSAIDs). In this regard, we will specifically test the hypothesis that the cyclooxygenase (COX) pathway and/or its eicosanoid products play a role in colorectal carcinogenesis. Colorectal cancer is the second leading cause of cancer related deaths in the United States. This year alone, approximately 55,000 Americans will die from this disease. Recent clinical research has revealed a 40-50% reduction in mortality from colorectal cancer in persons who take aspirin and other NSAIDs on a regular basis. Cyclooxygenase enzymes are known targets for NSAIDS. Two isoforms of cyclooxygenase have been characterized and they are referred to as Cyclooxygenase-1 (COX-1) and Cyclooxygenase-2 (COX-2) in this proposal. Previous work conducted by investigators involved in this program grant has demonstrated that there is a 2-50 fold increase in COX-2 expression in 85% of human colorectal adenocarcinomas and in 45-50% of adenomas. The goals of this program are to test the hypothesis that COX or its eicosanoid products play a role in colorectal carcinogenesis and to determine the molecular mechanisms by which NSAIDs prevent colorectal cancer. Here we provide an overview of the projects proposed to test this hypothesis and highlight how planned interactions among the investigators will aid significantly in the success of this program project. In addition, the role of COX-2 and prostaglandins in the pathogenesis of colorectal cancer is discussed, so as to provide a rationale for undertaking the projects that are proposed. There are four projects and three cores included in this revised Program Grant application.
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