Role of oxidative DNA damage in cancer initiation and promotion

Normal aerobic metabolism produces huge amounts of potentially dangerous oxidants, controlled by a variety of antioxidant systems. An imbalance between the generated and exogenously inflicted oxidants and the oxidant system is termed oxidative stress. Even without oxidative stress, i.e. under normal physiological conditions, the damage to vital cellular micromolecules, such as DNA, is extensive, amounting to hundreds of hits per cell per day. More than one hundred different oxidative modifications in DNA have been described. The hydroxylation of guanine in the 8-position is the most frequent and most mutagenic lesion described. The 8-hydroxylation of guanine leads to lack of base pairing specifically and misreading of the modified base and adjacent residues. The modifications to DNA are so frequent that extensive and specific repair is needed for survival. Indeed, multiple repair enzyme systems to mediate and remove/repair oxidative DNA modification are described. Within DNA, hot-spots of oxidative modification and subsequent mutation have been described, and some specificity appears as compared to other agents that can lead to modification of DNA, i.e. aflatoxin and benzo[a]pyrene. Numerous publications from epidemiology and intervention studies with antioxidants point at oxidative modification as an important factor in cancer development at certain sites. Yet, direct evidence linking oxidative DNA modification to cancer has not been published. With regard to antoxidant prevention of cancer no effective single substance has so far been identified.