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Changes in the Glutathione Content of Rat 9L Cells Induced by Treatment with the Ornithine Decarboxylase Inhibitor -Difluoromethylornithine¹

Brain Tumor Research Center for the Department of Neurological Surgery [K. J. H., D. F. D., L. J. M.], and the Departments of Radiation Oncology [D. F. D.] and Laboratory Medicine [L. J. M.], School of Medicine, University of California, San Francisco, California 94143

Treatment of 9L cells with the ornithine decarboxylase inhibitor -difluoromethylornithine (DFMO) depletes cells of putrescine and spermidine and sensitizes cells to the cytotoxic effects of the alkylating agent 1,3-bis(2-chloroethyl)-1-nitrosourea. Because depletion of intracellular levels of the sulfhydryl compound glutathione also increases the cytotoxicity of alkylating agents, the effect of DFMO on intracellular glutathione content was investigated to determine whether DFMO-induced sensitization could be explained by a sulfhydryl-related mechanism. Treatment of 9L cells with 1 mM DFMO caused no change in the glutathione concentration within 48 h; sensitization of cells to 1,3-bis(2-chloroethyl)-1-nitrosourea is generally studied after 48 h of treatment with DFMO. Incubation of cells with DFMO for longer periods caused an increase in glutathione that is related to the depletion of polyamines and not to a decrease in growth rate or a cell cycle effect. Increased glutathione content is not due to a decrease in glutathione catabolism, but rather to an apparent increase in the rate of synthesis of the tripeptide.

¹ Supported by NIH Program Project Grant CA-13525, a National Cooperative Drug Discovery Grant CA-37606, and the Aaron Silvera Cancer Research Fund.

² To whom requests for reprints should be addressed, at The Department of Laboratory Medicine, L-518, University of California, San Francisco, CA 94143.

Received 3/16/87. Revised 6/29/87. Accepted 7/14/87.