Increased levels of promutagenic etheno-DNA adducts in colonic polyps of FAP patients

Nonsteroidal anti-inflammatory drugs (NSAIDs) can regress adenomas in patie nts with familial adenomatous polyposis (FAP), and the mechanism involves i nhibition of cyclooxygenases (COX). Reactive intermediates formed during th e arachidonic acid cascade, notably by COX-2, which is upregulated in polyp s of FAP patients, may promote various stages of the polyp --> adenoma --> carcinoma sequence. Etheno-DNA adducts can be derived from reactive interme diates generated during arachidonic acid metabolism and lipid peroxidation. We tested this hypothesis in colonic polyps from FAP patients acid colorec tal tissue from cancer patients to see whether increased formation of ethen o-DNA adducts occurs. Using an ultra-sensitive and specific immunoaffinity/ P-32-postlabelling method, I,N-6-ethenodeoxyadenosine (epsilon dA) and 3,N- 4-ethenodeoxycytidine (epsilon dC) were quantitated in epithelial cell DNA from asymptomatic colon, FAP polyps and colon tumor tissues. Mean adduct le vels in FAP polyps were 65 epsilon dA/10(9) and 59 epsilon dC/10(9) parent nucleotides, being 2 to 3 times higher than in unaffected colon tissue (p < 0.02 for epsilon dA; p < 0.05 for epsilon dC), Adduct levels in colonic ep ithelia decreased in the order: FAP polyps > tumor-adjacent tissue > tumor, normal and tumor-distal tissue. Based on this study, requiring confirmatio n in a larger number of patients and in experimental models, we have demons trated the formation of promutagenic etheno-DNA adducts in adenomatous poly ps of FAP patients that may contribute to genetic instability and cancer pr ogression. Int. J. Cancer 87: 1-4, 2000. (C) 2000 Wiley-Liss, Inc.