THE EFFECTS OF SULINDAC ON COLORECTAL PROLIFERATION AND APOPTOSIS IN FAMILIAL ADENOMATOUS POLYPOSIS

Background & Aims: The mechanism by which sulindac causes regression o f adenomas in patients with familial adenomatous polyposis (FAP) is un clear. Conflicting data on the drug's effects on colorectal epithelial proliferation have been reported. An alternative mechanism, and one n ot previously studied, is via induction of colorectal epithelial cell apoptosis (programmed cell death). This hypothesis was tested by study ing the effects of sulindac on colorectal epithelial proliferation and apoptosis in patients with FAP. Methods: Cell proliferation was studi ed via immunohistochemistry for proliferating cell nuclear antigen in a group of 22 patients randomized to either sulindac (150 mg twice a d ay) or placebo in a previously published trial. The rectal epithelium from 7 additional patients with FAP treated with sulindac was examined by flow cytometry to assess changes in cell-cycle distribution and ap optosis. Results: Although sulindac caused a significant decrease in p olyp size and number, there was no significant change in cytokinetic v ariables or cell cycle distribution 3 months after treatment. However, the subdiploid apoptotic fraction was increased significantly 3 month s after treatment with sulindac (31.3% +/- 4.8% compared with 10% +/- 4.3% at baseline; P = 0.01). Conclusions: Our findings suggest that su lindac does not affect colorectal epithelial proliferation and that it s effects in patients with FAP may instead result from induction of ap optosis.