Abstract
The 1-(2-chloroethyl)-1-nitrosoureas are potent anti-cancer drugs1,2 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 DNA3; the second step, which occurs over a period of several hours in the absence of free drug3–6, could then form an inter-strand 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 strain6. Day and his coworkers (see refs 7, 8 and previous paper9) 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 chloro-ethylnitrosourea-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.
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Erickson, L., Laurent, G., Sharkey, N. et al. DNA cross-linking and monoadduct repair in nitrosourea-treated human tumour cells. Nature 288, 727–729 (1980). https://doi.org/10.1038/288727a0
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DOI: https://doi.org/10.1038/288727a0
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