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DNA Damage and Repair in the Bone Marrow of Rats Treated with Four Chloroethylnitrosoureas¹

Institute of Toxicology and Chemotherapy, German Cancer Research Centre, 6900 Heidelberg, Federal Republic of Germany [P. B.], and Department of Food Chemistry and Environmental Toxicology, University of Kaiserslautern, 6750 Kaiserslautern, Federal Republic of Germany [G. E.]

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 µmol/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.

¹ This work was supported in part by the German Ministry for Research and Technology (BMFT), Project PTB 038458.

² Supported by a Royal Society European Science Exchange Fellowship.

³ To whom requests for reprints should be addressed, at the Department of Food Chemistry and Environmental Toxicology University of Kaiserslautern, 6750 Kaiserslautern, Federal Republic of Germany.

Received 4/ 5/83. Accepted 10/25/83.

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