Familial adenomatous polyposis coli (FAP) is an autosomal dominant disorder characterized by the formation of hundreds of colorectal adenomatous polyps in young adults. Virtually all individuals with FAP will develop colorectal cancer if prophylactic colectomy is not performed. Moreover, many patients have upper gastrointestinal adenomas which predispose to duodenal carcinoma. Presently, the only effective therapy for FAP is colectomy and lifelong surveillance of the upper gastrointestinal tract. Our long term goal is to discover effective chemopreventative therapy for patients with FAP, representing a model which may provide basic insights into molecular regulation of the adenoma-carcinoma sequence in ordinary colorectal cancer. Sulindac, a nonsteroidal antiinflammatory prostaglandin inhibitor, has been reported anecdotally to resolve adenomatous polyps in 15 FAP patients. Our hypothesis is that sulindac can decrease growth of colorectal adenomas and the associated epithelial hyperproliferation in FAP patients.
Our specific aims are to: a) Administer sulindac to FAP patients in a randomized, placebo-controlled, double-blinded trial. b) Sequentially determine colorectal polyp number by video endoscopy and polyp volume by computerized image analysis. c) Sequentially assess in adenomas and nonpolypoid colorectal mucosa the activity of ornithine decarboxylase and S-adenosylmethionine decarboxylase (enzymes important in the regulation of the polyamine pathway), and epithelial proliferation index by immunohistochemistry with Ki-67 antibody to proliferating cell nuclear antigen.
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