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Antitumor Activity of the 3'-Chloroethylnitrosourea Analog of Thymidine and the Prevention by Co-administered Thymidine of Lethality but Not of Anticancer Activity¹

Departments of Pharmacology [T-S. L., P. H. F., J. C. M., W. H. P.] and Medicine [J. C. M.], Yale University School of Medicine, New Haven, Connecticut 08510

The effect of the 3'-nitrosourea analog of thymidine (3'-[3-(2-chloroethyl)-3-nitrosoureido]-3'-deoxythymidine; 3'-CTNU) on the growth of the murine L1210 and P388 leukemias in mice was investigated. A single injection of 3'-CTNU (40 mg/kg) was minimally toxic to mice bearing the L1210 leukemia and produced 60-day survivors.

The coadministration of thymidine did not prevent the initial loss of weight caused by 3'-CTNU but did prevent the lethality otherwise produced in non-tumor-bearing mice. A single dose of thymidine (2 g/kg) administered to L1210-bearing mice had no anticancer activity and when coadministered with 3'-CTNU had no deterimental effect on the potent antitumor effects of 3'-CTNU. Similar results were obtained against P388 leukemia.

The hematopoietic toxicity produced by the administration of 3'-CTNU to non-tumor-bearing mice, as evidenced by changes in the white blood cells, neutrophil, and agar diffusion chamber precursor cell concentrations in the hematocrit and in bone marrow cellularity, could not be prevented by thymidine. Therefore, the lethality produced by 3'-CTNU is probably not related to hematopoietic toxicity since the coadministration of thymidine completely prevented any lethality.

¹ This investigation was supported by Grants CH-115 and CH-196 from the American Cancer Society and CA-08341 from the National Cancer Institute.

² To whom requests for reprints should be addressed.

³ Present address: Department of Human Oncology, University of Wisconsin School of Medicine, Madison, Wis. 53792.

Received 9/30/81. Accepted 1/19/82.