Some of the pharmacological properties of a new class of compounds are described in which either a methyl- or a ehloroethyl-nitrosourea functionality is attached to the 3'-position of 3'-deoxythymidine (3'-MTNU and 3'-CTNU) or to the 5'-position of 5'-deoxythymidine (5'-MTNU and 5'-CTNU). The pharmacological effects of these thymidine analogs vary considerably. The dose-response curves for the inhibition of leukemic L1210 cell growth by the 5'-derivatives were similar to that for 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), being characterized by a shoulder region and a linear component. However, the corresponding curves for the 3'-derivatives were biphasic, being initially steep and linear followed by a shallow portion. Pyrimidine 2'-deoxyribonucleosides (thymidine, deoxyuridine or deoxycytidine), but not pyrimidine ribonucleosides or purine nucleosides, can specifically prevent and reverse the inhibition of cell growth caused by the 3'-analogs. In contrast, the inhibition of cell replication induced by 5'-CTNU or BCNU was not decreased by the addition of thymidine, deoxyuridine or deoxycytidine. The protective effect was dependent on the relative concentrations of the protecting pyrimidine deoxyribonucleoside and the 3'-nitrosourea. Of particular importance is the finding that the addition of deoxycytidine to L 1210 cells, treated previously for 24 hr with 3'CTNU, substantially reversed the growth inhibition, suggesting that competition for cellular transport is not the critical site of interaction and that alkylation may not be the primary mode of action. Soft agar cloning experiments revealed that deoxycytidine also protects L 1210 cells from the lethal effects of 3'-CTNU. The protective interaction is not unique to L 1210 cells since the growth inhibitory effects of 3'-CTNU on B 16 melanoma cells could also be reduced by deoxycytidine. Under physiological conditions, 3'-CTNU decomposes to generate alkylating and carbamoylating species. In addition, however, a stable cytotoxic compound, 3'-amino-3'-deoxythymidine, is also formed. This aminonucleoside is generated in sufficient quantities to contribute to the pharmacological actions of 3'-CTNU and may account for the specific protective interaction exerted by pyrimidine 2'-deoxyribonucleosides. © 1979.
