Exocyclic DNA adducts as oxidative stress markers in colon carcinogenesis: potential role of lipid peroxidation

H. Bartsch Ph.D., J. Nair Ph.D., R. Owen Ph.D.

German Cancer Research Center DKFZ, Division of Toxicology and Cancer Risk Factors, Heidelberg, Germany

AIM: Molecular pathways to colorectal cancer involve multiple genetic changes that may be caused by overexpression of reactive oxygen/nitrogen species in cancer-related genes. Our aim was to investigate, whether besides direct oxidative DNA-damage, etheno-DNA adducts could be induced in colon tissue via trans-4-hydroxy-2-nonenal, a major aldehyde generated by lipid peroxidation (LPO). METHODS: We analyzed the etheno adducts by a highly specific, ultrasensitive method involving immunoaffinity chromatography coupled with 32P-postlabeling (Nair et al., Carcinogenesis, 1995,) in affected colon epithelium from ulcerative colitis, Crohn's disease and familial adenomatous polyposis (FAP) and compared them with asymptomatic colon tissue. RESULTS: In all these cancer prone colon tissues the formation of markedly enhanced etheno adduct levels was demonstrated for the first time. Etheno-DNA adducts are promutagenic and cause genomic instability that could drive the inflamed colonic epithelia to malignancy. CONCLUSIONS: Etheno adducts appear promising biomarkers for i) quantifying increased DNA damage in early stages of colon carcinogenesis and for ii) verifying the efficacy of new antioxidants (e.g. Owen et al., Lancet Oncology, 2000) and chemopreventive regimens in lowering oxidative stress and related cancer risk.

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Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Predictive Markers.