Increased levels of promutagenic etheno-DNA adducts in colonic polyps of FAP patients.
Nonsteroidal anti-inflammatory drugs (NSAIDs) can regress adenomas in patients with familial adenomatous polyposis (FAP), and the mechanism involves inhibition of cyclooxygenases (COX). Reactive intermediates formed during the arachidonic acid cascade, notably by COX-2, which is upregulated in polyps of FAP patients, may promote various stages of the polyp --> adenoma --> carcinoma sequence. Etheno-DNA adducts can be derived from reactive intermediates generated during arachidonic acid metabolism and lipid peroxidation. We tested this hypothesis in colonic polyps from FAP patients and colorectal tissue from cancer patients to see whether increased formation of etheno-DNA adducts occurs. Using an ultra-sensitive and specific immunoaffinity/(32)P-postlabelling method, 1, N(6)-ethenodeoxyadenosine (straightepsilondA) and 3, N(4)-ethenodeoxycytidine (straightepsilondC) were quantitated in epithelial cell DNA from asymptomatic colon, FAP polyps and colon tumor tissues. Mean adduct levels in FAP polyps were 65 straightepsilondA/10(9) and 59 straightepsilondC/10(9) parent nucleotides, being 2 to 3 times higher than in unaffected colon tissue (p < 0.02 for straightepsilondA; p < 0.05 for straightepsilondC). Adduct levels in colonic epithelia decreased in the order: FAP polyps > tumor-adjacent tissue > tumor, normal and tumor-distal tissue. Based on this study, requiring confirmation in a larger number of patients and in experimental models, we have demonstrated the formation of promutagenic etheno-DNA adducts in adenomatous polyps of FAP patients that may contribute to genetic instability and cancer progression.
Schmid
K
K
Division of Toxicology and Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Nair
J
J
Winde
G
G
Velic
I
I
Bartsch
H
H
D000236:Adenoma / Q000235:genetics* / Q000378:metabolism*; D011125:Adenomatous Polyposis Coli / Q000235:genetics* / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003106:Colon / Q000378:metabolism; D003111:Colonic Polyps / Q000235:genetics* / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism*; D018736:DNA Adducts / Q000096:biosynthesis*; D003839:Deoxyadenosines / Q000096:biosynthesis; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000096:biosynthesis; D005260:Female; D006801:Humans; D015227:Lipid Peroxidation; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress
D018736:DNA Adducts; D003839:Deoxyadenosines; D003841:Deoxycytidine; C032221:1,N(6)-ethenodeoxyadenosine; C032222:3,N(4)-ethenodeoxycytidine