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Effect of Carbamoylation on the Repair of Nitrosourea-induced DNA Alkylation Damage in L1210 cells¹

Division of Medical Oncology, Vincent T. Lombardi Cancer Research Center, Georgetown University School of Medicine, Washington, D. C. 20007

The effect of nitrosourea carbamoylating activity on the repair of nitrosourea-induced DNA alkylation damage has been evaluated. Two methylnitrosoureas were investigated; streptozotocin, a C-2 glucose-substituted methylnitrosourea, and 3-ß-D-glucopyranosyl-1-methyl-1-nitrosourea (GMNU), a C-1 glucose analog. Streptozotocin has an alkylating activity (100%) similar to that of GMNU (92%) but a widely differing carbamoylating activity (streptozotocin produced 3% carbamoylation of [¹⁴C]lysine versus 42% produced by GMNU). L1210 cells after a 2-hr 0.5 mM incubation showed equivalent single-strand breaks, 1.77 ± 0.13 (S.E.)/1 x 10⁹ daltons with streptozotocin and 1.67 ± 0.03 for GMNU, measured by alkaline sucrose gradients. Following streptozotocin, full repair of these lesions was documented 8 hr after drug removal. In contrast, the repair of GMNU-induced damage was not complete for 12 hr. The cytotoxicity of the two drugs for L1210 cells, both in vitro using a colony-cloning assay and in vivo in mice, was not statistically different. Thus, although the carbamoylating activity of GMNU is associated with a delay in repair of single-strand breaks, the antitumor activity of this drug is not significantly increased by either the carbamoylating activity or the delay in repair of alkylated lesions. The similar alkylating activity, single-strand breaks, and L1210 cytotoxicity of streptozotocin and GMNU suggest that alkylating activity is the principal mediator of L1210 cytotoxicity.

¹ This investigation was supported in part by American Cancer Society Research Grant CH-13, and NIH Grant 1-RO1-CA-17583-02ET.

² To whom requests for reprints should be addressed.

Received 5/30/78. Accepted 9/29/78.