title: Chronic inflammation and oxidative stress in the genesis and perpetuation of cancer: role of lipid peroxidation, DNA damage, and repair.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Toxicology and Cancer Risk Factors, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. h.bartsch@dkfz.de
authors.forename: Helmut
authors.initials: H
authors.lastname: Bartsch
authors.forename: Jagadeesan
authors.initials: J
authors.lastname: Nair
mesh_terms: D002908:Chronic Disease; D018736:DNA Adducts / Q000737:chemistry / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D006801:Humans; D007249:Inflammation / Q000150:complications*; D015227:Lipid Peroxidation; D008107:Liver Diseases / Q000150:complications / Q000378:metabolism; D009369:Neoplasms / Q000209:etiology* / Q000235:genetics; D018384:Oxidative Stress; D012307:Risk Factors
chemical_list: D018736:DNA Adducts