DNA cross-linking and monoadduct repair in nitrosourea-treated human tumour cells
- 1 December 1980
- journal article
- Published by Springer Science and Business Media LLC in Nature
- Vol. 288 (5792), 727-729
- https://doi.org/10.1038/288727a0
Abstract
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.Keywords
This publication has 9 references indexed in Scilit:
- Defective repair of alkylated DNA by human tumour and SV40-transformed human cell strainsNature, 1980
- A chromatin factor in rat liver which destroys O6‐ethylguanine in DNAFEBS Letters, 1980
- DNA crosslinking and cytotoxicity in normal and transformed human cells treated with antitumor nitrosoureas.Proceedings of the National Academy of Sciences of the United States of America, 1980
- Human tumor cell strains defective in the repair of alkylation damageCarcinogenesis: Integrative Cancer Research, 1980
- Adaptive response to alkylating agents involves alteration in situ of O6-methylguanine residues in DNANature, 1979
- Quantitation of the adaptive response to alkylating agentsNature, 1979
- Human brain tumour cell strains with deficient host-cell reactivation of N-methyl-N′-nitro-N-nitrosoguanidine-damaged adenovirus 5Nature, 1979
- Mechanism of action of 2-haloethylnitrosoureas on DNA and its relation to their antileukemic propertiesBioorganic Chemistry, 1978
- Fractionation of DNA from mammalian cells by alkaline elutionBiochemistry, 1976