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Repair of DNA Alkylation Induced in L1210 Leukemia and Murine Bone Marrow by Three Chloroethylnitrosoureas¹

Division of Medical Oncology [J. D. A., D. C. G., K. D. T., P. S. S.], Department of Biochemistry [K. D. T.], and Department of Pharmacology [P. S. S.], Vincent T. Lombardi Cancer Research Center, Georgetown University School of Medicine, Washington, D. C. 20007

The removal of DNA adducts is an essential step of DNA repair following exposure to chloroethylnitrosoureas. Adduct removal was evaluated in both L1210 and murine bone marrow DNA for lesions induced by three chloroethylnitrosoureas. 1-(2-Chloroethyl)-3-cyclohexyl-1-nitrosourea, a marrow-toxic agent with high carbamoylating activity, was not removed in either system for at least 6 to 12 hr. These results were compared with those obtained with two glucose-linked chloroethylnitrosoureas, chlorozotocin and 1-(2-chloroethyl)-3-(ß-D-glucopyranosyl)-1-nitrosourea. Both of these agents have low marrow toxicity at therapeutic doses. Chlorozotocin, which has very low chemical carbamoylating activity, was found to permit approximately 40% removal of drug-derived DNA adducts in both systems within the first 6 hr and approximately 50% by 18 hr. The second glucose-linked analog, 1-(2-chloroethyl)-3-(ß-D-glucopyranosyl)-1-nitrosourea, has relatively high carbamoylating activity and was found to inhibit early removal of DNA adducts as effectively as does 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea. It would thus appear that the selective marrow-sparing property of the sugar-linked chloroethylnitrosoureas is not dependent upon carbamoylation-mediated differences in the rate and extent of DNA adduct removal. In view of the comparable therapeutic activity of the three drugs for L1210 leukemia, therapeutic efficacy does not appear to be impaired by the increased rate of adduct removal observed with chlorozotocin in this system.

¹ Supported by NIH Grant CA-17583 and American Cancer Society Grant CH-13d.

² To whom requests for reprints should be addressed, at Division of Medical Oncology, Georgetown University Hospital, 3800 Reservoir Road, N.W., Washington, D. C. 20007.

Received 10/28/81. Accepted 4/ 1/82.