Biological relevance of adduct detection to the chemoprevention of cancer.
Adducts arise from the chemical modification of bases in DNA or amino acids in proteins by toxic chemicals. Many chemicals known to be carcinogenic in humans have been shown to form adducts or to cause oxidative damage to genomic DNA in model systems. Biomarkers of carcinogenesis reflect biological events that take place between exposure to external or endogenous carcinogens and the subsequent development of cancer. Therapeutic intervention for the purpose of cancer chemoprevention may modify these biomarkers. In this article, the potential efficacy of DNA adducts as biomarkers of carcinogenesis and chemoprevention is discussed using criteria defined for phases of biomarker development. The sensitivity of adduct detection in histologically normal tissue offers opportunities for the early detection of carcinogenesis. Extensive evidence for aflatoxin B(1) adducts as biomarkers of risk and progression of hepatic carcinogenesis and for oxidative DNA adducts as biomarkers of the development of prostate carcinogenesis is reviewed together with the clinical trials measuring these adducts as biomarkers of the efficacy of chemoprevention. Favorable modification of oxidative DNA adducts by dietary intervention and chemoprevention has been demonstrated in preclinical and clinical studies. Protein adducts and DNA adducts in blood constituents or urine may act as useful surrogates for the target organ. Additional information regarding reliability, reproducibility, specificity, and confounding variables are required at the clinical level to validate adducts as suitable biomarkers of chemoprevention. "We do not administer antihypertensive drugs to patients in clinical trials without checking their blood pressure, so why should we give antioxidants without checking that they have decreased oxidant status.
Cancer Biomarkers and Prevention Group, Oncology Department, University of Leicester, Leicester Royal Infirmary, Leicester, United Kingdom. ras20@le.ac.uk
Ricky A
RA
Sharma
Peter B
PB
Farmer
D000080242:8-Hydroxy-2'-Deoxyguanosine; D016604:Aflatoxin B1 / Q000737:chemistry; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D014408:Biomarkers, Tumor; D002273:Carcinogens / Q000009:adverse effects; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism; D002471:Cell Transformation, Neoplastic; D002986:Clinical Trials as Topic; D004247:DNA / Q000737:chemistry; D018736:DNA Adducts; D004249:DNA Damage; D004260:DNA Repair; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004032:Diet; D006801:Humans; D007120:Immunochemistry; D008297:Male; D013058:Mass Spectrometry; D008956:Models, Chemical; D009369:Neoplasms / Q000378:metabolism; D018384:Oxidative Stress; D010100:Oxygen / Q000737:chemistry; D011471:Prostatic Neoplasms / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D011506:Proteins / Q000737:chemistry; D012306:Risk; D012680:Sensitivity and Specificity
D016588:Anticarcinogenic Agents; D000975:Antioxidants; D014408:Biomarkers, Tumor; D002273:Carcinogens; D018736:DNA Adducts; D011506:Proteins; D000080242:8-Hydroxy-2'-Deoxyguanosine; D004247:DNA; D016604:Aflatoxin B1; D003849:Deoxyguanosine; D010100:Oxygen