PRIMARY CHEMOPREVENTION IN ADENOMATOUS POLYPOSIS COLI

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Familial adenomatous polyposis coli (FAP) is an autosomal dominant syndrome due to germline alteration of the APC (Adenomatous Polyposis Coli) gene recently discovered on chromosome 5. FAP presents phenotypically by formation of hundreds of colorectal adenomatous polyps in children and young adults. Virtually all individuals with FAP will develop colorectal cancer if prophylactic colectomy is not performed. We and others have shown that sulindac, a prostaglandin inhibitor, can suppress established adenomatous polyps in FAP patients. Our long term goal is to discover effective chemopreventive therapy for patients with FAP, representing a model which may provide basic insights into the molecular regulation of the adenoma-carcinoma sequence in other high-risk cancer syndromes and ordinary colorectal cancer. Presymptomatic testing of at-risk patients to determine those genotypically affected by FAP due to germline mutation of the APC gene can now be done. Our hypothesis is that sulindac used as a chemopreventive agent can prevent the phenotypic expression of adenomas in genotypically affected patients with FAP. Our specific aims are to: l) Administer sulindac to genotypically affected but phenotypically unaffected FAP patients in a randomized, long-term, placebo-controlled, double-blinded trial. We will assess the tolerability of sulindac and the compliance in a young aged population by measurement of plasma sulindac levels, and evaluate efficacy of sulindac by sequentially monitoring for polyp development, polyp number and size using by video endoscopy. 2) Sequentially assess in flat and polypoid colorectal mucosa the activity of ornithine decarboxylase and S- adenosylmethionine decarboxylase (enzymes in the polyamine pathway), epithelial proliferation by immunohistochemistry for proliferating cell nuclear antigen, and prostaglandin levels to determine mechanism(s) of sulindac effect.