Comparison of sister-chromatid exchange induction caused by nitrosoureas that alkylate or alkylate and crosslink DNA.
We have investigated the induction of sister-chromatid exchanges (SCEs) in 9L rat brain tumor cells treated with the alkylating agent 1-ethyl-1-nitrosourea (ENU) and 3-(4-amino-2-methyl-5-pyrimidinyl)methyl-1-(2-chloroethyl)-1-nitrosourea (ACNU), an agent that both alkylates and crosslinks DNA. Induction of SCEs by ACNU was found to be 143-fold greater than for ENU. However, on an equimolar basis, the alkylation of DNA by 14C-ACNU was approximately 3.2-fold higher than for 14C-ENU. After correction for this difference was made, the induction of SCEs by ACNU was calculated to be 45-fold greater than for ENU. While DNA alkylation products formed by ACNU and ENU are similar, the chloroethyl alkylation product(s) of ACNU can form DNA-interstrand crosslinks; the ethyl alkylation product(s) of ENU cannot. Based on these findings, we propose that the increased induction of SCEs caused by ACNU is a result of the formation of DNA interstrand crosslinks.
D000477:Alkylating Agents / Q000494:pharmacology; D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics; D002478:Cells, Cultured; D003432:Cross-Linking Reagents / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D005038:Ethylnitrosourea / Q000494:pharmacology*; D015376:Nimustine; D009607:Nitrosourea Compounds / Q000494:pharmacology*; D051381:Rats; D012854:Sister Chromatid Exchange / Q000187:drug effects*
D000477:Alkylating Agents; D003432:Cross-Linking Reagents; D009607:Nitrosourea Compounds; D015376:Nimustine; D004247:DNA; D005038:Ethylnitrosourea