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

Nature. 1980 Dec 25;288(5792):727-9. doi: 10.1038/288727a0.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Cell Line
  • Cell Transformation, Neoplastic / metabolism
  • Cross-Linking Reagents
  • DNA Repair*
  • DNA, Neoplasm / metabolism*
  • Ethylnitrosourea / analogs & derivatives
  • Ethylnitrosourea / pharmacology*
  • Humans
  • Methylation
  • Mutation
  • Nitrosourea Compounds / pharmacology*
  • Peptide Hydrolases / metabolism


  • Cross-Linking Reagents
  • DNA, Neoplasm
  • Nitrosourea Compounds
  • 1-(2-chloroethyl)-1-nitrosourea
  • Peptide Hydrolases
  • Ethylnitrosourea