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Methylazoxyprocarbazine, the Active Metabolite Responsible for the Anticancer Activity of Procarbazine against L1210 Leukemia¹

Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, Utah 84112 [D. S. S., G. S. Y.]; VA Medical Center, 500 Foothill Boulevard, Salt Lake City, Utah 84148 [W. G. H.]; and College of Pharmacy, Washington State University, Pullman, Washington 99164-6510 [M. G. H., J-Y. J., B. D. T., G. G. M.]

Procarbazine is a 1,2-disubstituted hydrazine derivative that is used to treat human leukemias. The anticancer activity of procarbazine results from bioactivation to reactive intermediates. It is first oxidized to azoprocarbazine and further N-oxidized to a mixture of methylazoxyprocarbazine and benzylazoxyprocarbazine isomers. In this study the azoxyprocarbazine isomers were synthesized and purified. The cytotoxic effect of the metabolites on the L1210 murine leukemia cell line were then evaluated in vitro by use of a colorimetric assay using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide. The results of this study showed that the methylazoxyprocarbazine isomer was the most cytotoxic metabolite (IC₅₀, 0.2 mM). The benzylazoxy isomer had an insignificant cytotoxic effect, and a mixture of the two isomers was intermediate in effectiveness. This assay, however, could not be used to determine the cytotoxicity of procarbazine since the drug itself (not the live cells) reduced the dye. A soft-agar clonogenic assay demonstrated that procarbazine was cytotoxic only at higher concentrations (IC₅₀, 1.5 mM) than methylazoxyprocarbazine (IC₅₀, 0.15 mM). The effect of procarbazine and its metabolites on the survival of L1210 tumor-bearing mice was determined, and methylazoxyprocarbazine was again the most effective compound. These studies demonstrate that the methylazoxyprocarbazine metabolite is probably the major cytotoxic intermediate involved in the mechanism of anticancer action of procarbazine.

¹ Supported in part by USPHS Grant CA35763, awarded by the National Cancer Institute. G. S. Y. is a USPHS Research Career Development Awardee (Grant HL02119).

² To whom requests for reprints should be addressed at Department of Pharmacology and Toxicology, 112 Skaggs Hall, University of Utah, Salt Lake City, Utah 84112.

Received 11/ 7/88. Accepted 2/ 7/89.

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