ROLE OF OXIDATIVE DNA-DAMAGE IN CANCER INITIATION AND PROMOTION

Normal aerobic metabolism produces huge amounts of potentially dangero us oxidants, controlled by a variety of antioxidant systems. An imbala nce between the generated and exogenously inflicted oxidants and the o xidant system is termed oxidative stress. Even without oxidative stres s, i.e. under normal physiological conditions, the damage to vital cel lular micromolecules, such as DNA, is extensive, amounting to hundreds of hits per cell per day. More than one hundred different oxidative m odifications in DNA have been described. The hydroxylation of guanine in the 8-position is the most frequent and most mutagenic lesion descr ibed. The 8-hydroxylation of guanine leads to lack of base pairing spe cifically and misreading of the modified base and adjacent residues. T he modifications to DNA are so frequent that extensive and specific re pair is needed for survival. Indeed, multiple repair enzyme systems to mediate and remove/repair oxidative DNA modification are described. W ithin DNA, hot-spots of oxidative modification and subsequent mutation have been described, and some specificity appears as compared to othe r agents that can lead to modification of DNA, i.e. aflatoxin and benz o[ a] pyrene. Numerous publications from epidemiology and intervention studies with antioxidants point at oxidative modification as an impor tant factor in cancer development at certain sites. Yet, direct eviden ce linking oxidative DNA modification to cancer has not been published . With regard to antoxidant prevention of cancer no effective single s ubstance has so far been identified. (C) 1998 Rapid Science Ltd.