Oxidative stress and lipid peroxidation-derived DNA-lesions in inflammation driven carcinogenesis
Division of Toxicology and Cancer Risk Factors, German Cancer Research Center, Heidelberg, Germany
During chronic inflammatory processes an excess of ROS/RNS and DNA-reactive aldehydes from lipid peroxidation (LPO) are produced, which deregulate cellular homeostasis and can drive normal cells to malignancy. Etheno (e)-modified DNA bases are generated by reactions of DNA with a major LPO product, trans-4-hydroxynonenal. AIM: We are investigating steady state levels of e-DNA adducts in organs, blood or urine from patients with diseases and conditions that predispose malignancies, especially when related to persistent inflammatory processes. METHODS: We have developed sensitive and specific methods for the detection of e-DNA-adducts (edA, edC) in vivo. Adducts are quantitated in DNA by an immunoaffinity/32P-postlabelling procedure (Nair et al. 1995) or by immunohistochemistry (Yang et al. 2000). edA in human urine is measured by an immunoaffinity-HPLC-fluorescence method (Nair 1999). RESULTS: Hepatic e-adduct levels were significantly elevated in patients with Wilson's disease and primary hemochromatosis. Excess storage of copper/iron causing oxidative stress and LPO-derived DNA-damage, are implicated in disease pathogenesis as confirmed by studies in LEC-rats, a model for Wilson's disease. edA in nuclei of human liver cells (needle biopsies) was quantified by our immunohistochemical method. Patients with hepatitis, fatty liver, fibrosis and cirrhosis (all mainly due to alcohol abuse) were compared with asymptomatic livers. Excess hepatic DNA-damage was seen in all patients, except the group with hepatitis. edA excreted in urine was measured by an immunoaffinity-HPLC-fluorescence method in HBV-infected male Thai patients diagnosed with chronic hepatitis, cirrhosis and hepatocellular carcinoma (Nair et al. 2002). As compared to asymptomatic HBV-carriers, patients had 20 to 90-fold increased urinary edA levels. CONCLUSIONS: e-DNA adducts should be explored as potential marker for liver disease progression in HBV/HBC carriers and in other inflammatory cancer-prone diseases. Also the efficacy of human chemoprevention/intervention studies could be verified by using our non-invasive urine assay; its applicability in a field study has been demonstrated (Hanaoka et al. 2002).
Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Nice, France; February 7 - 10, 2004; in plenary session 801 (Predictive markers & validation).