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Chronic inflammation and oxidative stress in the genesis and perpetuation of cancer: role of lipid peroxidation, DNA damage, and repair

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Abstract

Background and aims

Chronic inflammation, induced by biological, chemical, and physical factors, was associated with increased risk of human cancer at various sites. Chronic inflammatory processes induce oxidative/nitrosative stress and lipid peroxidation (LPO), thereby generating excess reactive oxygen species (ROS), reactive nitrogen species (RNS), and DNA-reactive aldehydes. Miscoding etheno- and propano-modified DNA bases are generated inter alia by reaction of DNA with these major LPO products. Steady-state levels of LPO-derived (etheno-) DNA adducts in organs affected by persistent inflammatory processes were investigated as potential lead markers for assessing progression of inflammatory cancer-prone diseases.

Results

Using ultrasensitive and specific detection methods for the analysis of human tissues, cells, and urine, etheno-DNA adduct levels were found to be significantly elevated in the affected organs of subjects with chronic pancreatitis, ulcerative colitis, and Crohn’s disease. Patients with alcohol-related liver diseases showed excess hepatic DNA damage progressively increasing from hepatitis, fatty liver, to liver cirrhosis. Ethenodeoxyadenosine excreted after DNA repair in urine of hepatitis B virus-related chronic hepatitis and liver cirrhosis patients was increased up to 90-fold. Putative mechanisms that may control DNA damage in inflamed tissues including impaired or imbalanced DNA repair pathways are reviewed.

Conclusion

Persistent oxidative/nitrosative stress and excess LPO are induced by inflammatory processes in a self-perpetuating process and cause progressive accumulation of DNA damage in target organs. Together with deregulation of cell homeostasis, the resulting genetic changes act as driving force in chronic inflammation-associated human disease pathogenesis. Thus steady-state levels of DNA damage caused by ROS, RNS, and LPO end products provide promising molecular signatures for risk prediction and potential targets and biomarkers for preventive measures.

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Acknowledgements

The authors greatly acknowledge the contributions and collaborative efforts by X. Sun, A. Frank, N. Frank, Y. Yang, and late C. Ditrich (DKFZ, Heidelberg); A. Barbin and Y Guichard (Lyon, France); G. Fürstenberger (DKFZ, Heidelberg); S. Tannenbaum and G. Wogan (Cambridge, USA); G. Winde (Herford, Germany); P. Srivanatakul (Bangkok, Thailand); F. Gansauge and H. Beger (Ulm, Germany); P. Dolora (Florence, Italy); and H.K. Seitz (Heidelberg, Germany). S. Fuladdjusch is thanked for excellent secretarial help. Work was in part supported by EU contracts ENV4-CT97-0505 and QLK4-CT2000-00286.

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Bartsch, H., Nair, J. Chronic inflammation and oxidative stress in the genesis and perpetuation of cancer: role of lipid peroxidation, DNA damage, and repair. Langenbecks Arch Surg 391, 499–510 (2006). https://doi.org/10.1007/s00423-006-0073-1

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