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Non-steroidal anti-inflammatory drugs, e.g. sulindac have been extensively studied for chemoprevention in familial adenomatous polyposis, but not in hereditary non-polyposis colorectal cancer (HNPCC). We evaluated these effects in HNPCC using surrogate end-points for cancer risk. In a randomised double-blind cross-over study, 22 subjects (9 female; age 30-66 years, mean 44), all ascertained or probable mutation carriers for HNPCC, were included. Sulindac 150 mg b.i.d. and placebo were given for 4 weeks each, with 4 weeks in between, with biopsies taken from ascending, transverse and sigmoid colon and rectum by colonoscopy after both periods. Proliferation was determined by Ki-67 staining and apoptosis by staining of cytokeratin 18 cleavage products. Expression of cyclins B1, D3 and E and p21, p27, bax, bcl2 and cox-2 was studied immunohistochemically. Proliferation was higher during sulindac treatment than drug placebo treatment in ascending and transverse colon, but not in sigmoid and rectum. Apoptosis was not affected. Besides an increase in cyclin D3, no differences were found in expression of regulating proteins in the proximal colon. Conclusion: Sulindac induces an increase in epithelial cell proliferation in the proximal colon of subjects with HNPCC. Since colorectal cancer predominantly arises in the proximal colon in HNPCC, these results cast doubts on the potential chemopreventive effects of sulindac in HNPCC. (C) 2007 Elsevier Ltd. All rights reserved.