The ultimate goal of this project is to identify safe chemopreventive agents to reduce morbidity and mortality from sporadic colorectal neoplasia and provide basic insights into the genetic and molecular causation of the adenoma-carcinoma sequence. We will evaluate agents and characterize their mechanisms of action in the multiple intestinal neoplasia (MIN) mouse model and patients with familial adenomatous polyposis (FAP). MIN mice and FAP patients have germline mutation of the adenomatous polyposis col (APC) gene and are therefore ideal models for the somatic APC mutations responsible for initiation of sporadic colorectal tumors.
The specific aims of our project are: l. Administer the selective cyclooxygenase (COX-2) inhibitors SC-58635 and SC-49046 to MIN mice and evaluate tumor outcome and appropriate biomarkers. As primary endpoint we will assess numbers of tumors. Sizes of tumors, COX-2 expression, prostaglandin levels, epithelial proliferation rates, and apoptotic indices will also be determined. 2. Administer the histamine type 2 (H2) receptor blocker cimetidine to MIN mice and evaluate tumor outcome and appropriate biomarkers. As primary endpoint we will assess numbers of tumors. Sizes of tumors, histamine levels, numbers and types of tumor-infiltrating lymphocytes, cytokine profiles, mucosal DNA adducts, serum gastrin, epithelial proliferation rates, and apoptotic indice will also be determined. We will compare cimetidine to other H2 blockers (ranitidine and famotidine) and to the proton pump inhibitor omeprazole. 3. Administer to MIN mice a combination of two candidate chemopreventive agents with different mechanisms of effects identified in Specific Aims #1 and #2 and evaluate tumor outcome and associated biomarkers. 4. Administer candidate chemopreventive agent(s) to FAP patients in a randomized, sulindac-controlled, double-blinded, crossover trial and sequentially monitor for polyp number by video endoscopy. We will also sequentially assess polyp size and appropriate biomarkers in adenomas and colorectal mucosa.
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