DNA cross-linking and monoadduct repair in nitrosourea-treated human tumour cells

Abstract

The 1-(2-chloroethyl)-1-nitrosoureas are potent anti-cancer drugs which produce DNA interstrand cross-links in a 2-step reaction sequence. The 1st step was proposed to be an addition of a chloroethyl group to a guanine-O6 position of DNA; the 2nd-step, which occurs over 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 chlorethyl monoadducts and the formation of interstrand cross-links allows time for a DNA repair mechanism, capable of removing the monoadducts, to prevent the cross-linking. This mechanism was proposed to account for a difference in interstrand cross-linking between a normal and a transformed human cell strain. Some human tumor cell strains (designated Mer- phenotype) are deficient in the ability to repair O6-methylguanine lesions in DNA. The repair function that removes O6-methylguanine residues from DNA might also remove chloroethyl monoadducts and hence prevent chloroethylnitrosourea-induced interstrand cross-linking. Evidence is presented that supports this hypothesis and indicates that the O6-methylguanine repair confers resistance to cell killing by chloroethylnitrosourea.