DNA Repair and Carcinogenesis by Alkylating Agents

There is now general acceptance that most, but not all, chemical carcinogens initiate a change to neoplastic growth by virtue of their interaction with DNA. This DNA damage then leads to the alteration of the activity of certain critical genes by inducing either mutations or an increased frequency of gene rearrangement which, in turn, results in abnormal regulation of gene expression. Although multiple mutations may be required to produce neoplastic growth, and the rate and frequency of progression towards neoplasia are greatly influenced by the extent of exposure to tumor promoters, there is good evidence that the formation and persistence of DNA damage correlates with the potency of a number of chemical carcinogens. These studies suggest that DNA repair processes, if sufficiently active and rapid, can provide a means to reduce the likelihood that exposure to a carcinogen might initiate a tumor. Numerous laboratory investigations, some of which are discussed in this chapter, are consistent with this hypothesis. There is also abundant evidence from epidemiological studies of the increased incidence of cancer in individuals suffering from heritable diseases involving defects in DNA repair. Such findings are consistent with the concept that such repair processes play a major role in minimizing the risk associated with environmental exposure to carcinogens.