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Mutagenic and Chemotherapeutic Activity in L1210 Leukemia of Several Monofunctional Alkylating Agents¹

Memorial Sloan-Kettering Cancer Center, New York, New York 10021

The mutagenic and chemotherapeutic activities of the following monofunctional alkylating agents were compared in vivo: ß-chloroethylamine, dimethyl- and diethylaminoethyl chloride; methyl- and ethylmethanesulfonate; methyl- and ethylnitrosourea; and procarbazine. The bifunctional alkylating agent diethylamine 2,2'-dichloro-N-methyl-hydrochloride was used as reference. The alkylating activity was assessed by reacting with 4-(p-nitrobenzyl)pyridine, and antitumor activity was determined against L1210 in vitro and in vivo. The L1210 response, which is consistent with useful alkylating reactivity, was very marked with the two nitrosoureas and procarbazine. The nitrosoureas and, to some extent, procarbazine decreased the tumorigenicity of L1210 leukemia as evidenced by the increase in survival times with increasing numbers of treatment generations. After treatment for about five transfers (10⁶ cells i.p.) with methylnitrosourea (40 mg/kg i.p. on Days 1, 3, and 5), the untreated control mice consistently survived free of tumor, whereas the treated mice died before Day 30. After treatment with ethylnitrosourea (80 mg/kg), the survival times also increased but more in the treated than in the corresponding control groups. Methylnitrosourea was most efficient in increasing the survival times and abolishing tumor transplantability. Antigenic change and loss of growth potential presumably were the reason for this increase in survival time, as indicated by tests in X-irradiated and nude mice. The fact that nitrosoureas and triazenes, besides reducing tumorigenicity, have similarities in their chemistry in that they decompose or are metabolically converted into diazohydroxides and then to carbonium ions is possibly of significance.

¹ Supported by National Cancer Institute Grants CA 18856 and CA 08748 and by the Elsa U. Pardee Foundation.

² To whom requests for reprints should be addressed.

Received 5/14/84. Accepted 10/ 9/84.