The overall objective of this research program is to evaluate whether treatment with ursodeoxycholic acid (UDCA) can reduce the incidence and mortality of colorectal cancer which is the second leading cause of cancer death in the United States with 53,000 fatalities in 1993. Adenomatous colon polyps are a recognized precursor of colorectal cancer and recent efforts at cancer prevention have focused on their early detection and removal by colonoscopy. However this approach is problematic, owing to the expense and risk associated with colonoscopy and the fact that colon adenomas tend to recur. The recent description of molecular genetic changes that characterize progression from an adenoma to carcinoma raises the possibility that genetic analysis of peripheral blood leukocytes may identify persons at increased risk for future development of colon cancer. Individuals so identified, as well as the large patient population with a history of a prior sporadic colorectal adenoma, presumably would benefit from a treatment intervention which suppresses the effects of endogenous and environmental cancer promoters on the colonic mucosa. Over the past 50 years, a variety of epidemiological and experimental studies have strongly supported an important role for fecal secondary bile acids, especially deoxycholic acid (DCA), in promoting colon cancer. UDCA is a tertiary bile acid normally present in small amounts in human bile. In contrast to DCA, UDCA is not toxic to colonic mucosa and does not promote colon cancer in experimental animals. To the contrary, it is strongly protective. The goal of this proposal is to determine in humans whether UDCA treatment will suppress recurrence of colorectal adenomas and/or the development of adverse characteristics (e.g.. genetic alterations and/or DNA aneuploidy) associated with increased cancer risk in any recurrent adenomas. The proposed study is a prospective, randomized double-blind Phase Ill trial in which 1200 patients with resected colorectal adenomas will be assigned to treatment for 3 years with UDCA (8-10 mg/kg/day) or placebo. The size, type, number, location, and DNA ploidy status in colon adenomas removed at the qualifying colonoscopy will be compared with baseline fecal and plasma bile acids. The same parameters (excluding DNA ploidy) will be evaluated for any polyps found and removed by colonoscopy at completion of UDCA treatment. The effects of UDCA on other surrogate endpoint biomarkers, including colonic epithelial cell proliferation (e.g., PCNA) and the expression of protein kinase C isotypes and/or enzyme activity will be evaluated in normal flat mucosa obtained by rectal mucosal biopsy in a 25% subset of subjects and the results compared with bile acid concentrations in plasma and stool. UDCA side effects and treatment compliance will also be evaluated. The study has sufficient power to determine if UDCA is likely to be an effective chemopreventive agent for use in persons at increased risk for colorectal adenoma recurrence and whether it beneficially effects surrogate endpoint biomarkers of colon cancer risk.
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