DNA cross-linking and monoadduct repair in nitrosourea-treated human tumour cells.
The 1-(2-chloroethyl)-1-nitrosoureas are potent anti-cancer drugs which produce DNA inter-strand cross-links in a two-step reaction sequence. The first step was proposed to be an addition of a chloroethyl group to a guanine-O6 position of DNA; the second step, which occurs over a period of several hours in the absence of free drug, could then form an interstrand cross-link by the slow reaction of the bound chloroethyl group with a nucleophilic site on the opposite DNA strand. The delay between the formation of chloroethyl monoadducts and the formation of inter-strand cross-links allows time for a DNA repair mechanism, capable of removing the monoadducts, to prevent the cross-linking. We recently proposed this mechanism to account for a difference in inter-strand cross-linking between a normal and a transformed human cell strain. Day and his coworkers (see refs 7, 8 and previous paper) found that some human tumour cell strains (designated Mer- phenotype) are deficient in the ability to repair O6-methylguanine lesions in DNA. We therefore hypothesized that the repair function that removes O6-methylguanine residues from DNA would also remove chloroethyl monoadducts and hence prevent chloroethylnitrosourea-induced inter-strand cross-linking. We now present evidence that supports this hypothesis and indicates also that the O6-methylguanine repair confers resistance to cell killing by chloroethylnitrosourea.
D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D003432:Cross-Linking Reagents; D004260:DNA Repair; D004273:DNA, Neoplasm / Q000378:metabolism*; D005038:Ethylnitrosourea / Q000031:analogs & derivatives / Q000494:pharmacology*; D006801:Humans; D008745:Methylation; D009154:Mutation; D009607:Nitrosourea Compounds / Q000494:pharmacology*; D010447:Peptide Hydrolases / Q000378:metabolism
D003432:Cross-Linking Reagents; D004273:DNA, Neoplasm; D009607:Nitrosourea Compounds; C017139:1-(2-chloroethyl)-1-nitrosourea; D010447:Peptide Hydrolases; D005038:Ethylnitrosourea