VARIABILITY IN DNA-REPAIR AND INDIVIDUAL SUSCEPTIBILITY TO GENOTOXINS

DNA repair is an important mechanism of cellular protection from the e ffects of genotoxic chemicals. Although extensive evidence from studie s in experimental systems indicates that variation in DNA repair can s ignificantly influence susceptibility to genotoxins, corresponding stu dies in human populations are so far limited, mainly because of method ological difficulties. One system, using observations of the accumulat ion and repair of DNA damage in cancer patients treated with alkylatin g cytostatic drugs, has provided useful information for assessing the effects of interindividual variation in DNA repair activity on the ind uction of genotoxic effects in humans. The most detailed studies of th is kind have been carried out on patients with cancer (i.e., Hodgkin d isease, malignant melanoma) treated with the methylating cytostatic dr ugs procarbazine or dacarbazine; these studies have provided detailed information on dose-response relationships. They have also demonstrate d the protective role of the repair enzyme O-6-alkylguanine-DNA alkylt ransferase against the accumulation of the premutagenic methylated DNA lesion O-6-methylguanine in patients' DNA. Given the strong evidence that exposure of the general population to environmental methylating a gents may be extensive, as indicated by the frequent discovery of meth ylated DNA adducts in human DNA, data on DNA damage and repair in alky lating drug-treated patients and their modulation by host factors may prove useful in efforts to assess the possible carcinogenic risks pose d by exposure to environmental methylating agents.