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The antitumor compound ACNU (1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitroso ure a hydrochloride) is widely used for treatment of malignant brain tumors. The authors have investigated the mechanism of acquisition of ACNU resistance at the cellular level by isolating ACNU-resistant mutants from V79 Chinese hamster cells and C6 rat glioma cells after treatment of the cells with ACNU or other alkylating agents. In V79 Chinese hamster cells, ACNU at 1 to 4 micrograms/ml caused dose-dependent induction of drug-resistant mutants to ACNU (10 micrograms/ml) and 8-azaguanine (20 micrograms/ml), but not to ouabain (1 mM). Values for the mean lethal dose of ACNU-resistant mutants were 2.4 to 17.2 times those of the parent V79 cells. The ACNU-resistant phenotype was stable during an observation period of 13 weeks. The ACNU seemed to have a specific effect in inducing ACNU-resistant mutations, because no ACNU-resistant mutations were induced by treatment of the cells with other known mutagens, such as N-methyl-N'-nitro-N-nitrosoguanidine, methylmethanesulfonate, and ethylmethanesulfonate. The C6 rat glioma cells also showed a significant mutagenic response to ACNU, producing ACNU- and 5-fluorouracil-resistant mutants. The present results have the important therapeutic and mechanistic implication that ACNU is a potent mutagen and induces mutants that are resistant to ACNU and to other drugs.
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