) Colorectal cancer is the second leading cause of cancer deaths in the U.S. and therefore, a major public health issue. Prevention or control of colorectal cancer could result in a significant saving of lives and health care dollars. Several studies have reported a 40-50% reduction in the risk of developing colorectal cancer in persons who take nonsteroidal anti-inflammatory drugs (NSAIDs), like aspirin, on a regular basis. One possible mechanism for this NSAID-effect to reduce cancer risk is via the inhibition of cyclooxygenase enzymes. Two isoforms of this enzyme have been characterized, which will be referred to as cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) in this proposal. COX-2 expression is markedly increased in 40-50% of adenomas and in 85-90% of human colorectal adenocarcinomas, while COX-1 levels remain unchanged. Most of the NSAIDs examined to date in clinical studies inhibit both the COX-1 and COX-2 enzymes. Controversy exists over the role of cyclooxygenase enzymes in the prevention of colorectal cancer. Some groups do not feel that the cyclooxygenase pathway plays an important role because cell culture experiments have shown that one NSAID, lacking COX inhibitory activity, can induce apoptosis in cells which lack expression of the COX-2 gene. These effects are only seen at drug concentrations above the range of 400-750 micromolar. Nonetheless, this work points out the importance of maintaining an objective approach and designing experiments to evaluate the mechanisms involved in the chemoprotective activity of NSAIDS. To address this controversy, we plan to carry out the studies described in Project 1 to determine the relative importance of the cyclooxygenase pathway in the regulation of programmed cell death by NSAIDs. We plan to employ animal models to test the hypothesis that COX-2 and/or COX-1 may be relevant targets of NSAID drugs in the prevention of colorectal cancer.
Our specific aims are to: 1) Utilize xenograft models in athymic nude mice to evaluate the mechanism by which selective and non-selective NSAIDs cause regression of tumors positive and negative for COX-2 expression, 2) Utilize mouse lines lacking either COX-1 or COX-2 expression to determine the relative importance of the presence of either enzyme in NSAID-induced apoptosis in the intestine, 3) Crossbreeding of COX-1 and COX-2 null mice with Min and APC mutant mice to determine the importance of COX enzymes in intestinal tumorigenesis and whether treatment with NSAIDs could further reduce tumor number in COX deficient mice. By utilizing these approaches our overall goal is to better understand the mechanisms involved in the chemoprevention of colorectal cancer and whether highly selective NSAIDs could be effective agents in the chemoprevention of intestinal cancer.
Showing the most recent 10 out of 336 publications
