Drug resistance and DNA repair.
DNA repair confers resistance to anticancer drugs which kill cells by reacting with DNA. A review of our current information on the topic will be presented here. Our understanding of the molecular biology of repair of 0(6)-alkylguanine adducts in DNA has advanced as a result of the molecular cloning of the E. coli ada gene but the precise role of this lesion in the cytotoxic effects of alkylating agents in mammalian cells is not completely understood. Less progress has been made in understanding the enzymology and molecular biology of DNA cross-link repair even though such lesions are important for the cytotoxic effects of the widely used bifunctional alkylating agents and platinum compounds. It is evident that drug sensitive or resistant phenotypes are as highly complex as are the effects of DNA damage on cell metabolism and various aspects of these effects are discussed. Few clear correlations have been made between quantitative differences in DNA repair capacity and cellular sensitivity but assays which were developed to measure fidelity and intragenomic heterogeneity in DNA repair are beginning to be applied. Such studies may reveal subtle differences between sensitive and resistant cell lines. The molecular cloning of human DNA repair genes by transfection into drug sensitive rodent cells has been attempted. Some success has been achieved in this area but the functions of the cloned genes have yet to be identified.
Fox
M
M
Paterson Institute for Cancer Research, Christie Hospital and Holt Radium Institute, Manchester, UK.
Roberts
J J
JJ
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D004249:DNA Damage; D004260:DNA Repair; D004351:Drug Resistance; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy; D014162:Transfection
D000970:Antineoplastic Agents