title: DNA damage and repair in the bone marrow of rats treated with four chloroethylnitrosoureas.
abstract: DNA is considered to be an important target for the antitumor and toxic properties of the chloroethylnitrosoureas. Since the main target for their dose-limiting toxicity and the antileukemic efficacy is believed to be the bone marrow, we have compared the formation and subsequent removal of DNA-DNA interstrand cross-links in the bone marrow of rats which had received a single i.p. injection (100 mumol/kg) of four chloroethylnitrosoureas. The kinetics of cross-link removal was identical for chlorozotocin, which is known to have low chemical carbamoylating activity, to that of 1,3-bis(2-chloroethyl)-1-nitrosourea, a drug with a relatively high carbamoylating capacity. The differential bone marrow toxicity exhibited by these two agents could not, therefore, be explained by a carbamoylation-mediated difference in the rate and extent of DNA-DNA interstrand cross-link removal. The peak level and overall magnitude of cross-links were, however, found to vary considerably with the chemical structure of the analogues. Both 1-(2-chloroethyl)-1-nitroso-3-(methylene-carboxamido)urea and 1-(2-hydroxyethyl)-3-(2-chloroethyl)-3-nitrosourea, were much more effective in inducing interstrand cross-links than 1,3-bis(2-chloroethyl)-1-nitrosourea or chlorozotocin. This differential cross-linking did not, however, parallel the single-dose acute toxicity of these agents but reflected to a greater extent differences in their antileukemic activity. Considering the widely differing biological properties of this class of compounds, the measurement of DNA-DNA interstrand cross-linking in vivo might prove relevant in the evaluation of novel nitrosoureas.
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000187:drug effects*; D002273:Carcinogens / Q000494:pharmacology*; D002330:Carmustine / Q000494:pharmacology; D004260:DNA Repair; D005038:Ethylnitrosourea / Q000031:analogs & derivatives / Q000494:pharmacology*; D005260:Female; D009607:Nitrosourea Compounds / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013311:Streptozocin / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D002273:Carcinogens; D009607:Nitrosourea Compounds; C024218:acetamido-CNU; C007028:chlorozotocin; D013311:Streptozocin; C013876:elmustine; D005038:Ethylnitrosourea; D002330:Carmustine