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Decreased Cytotoxicity of cis-Diamminedichloroplatinum(II) by -Difluoromethylornithine Depletion of Polyamines in 9L Rat Brain Tumor Cells in Vitro¹

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

Before treatment with the cytotoxic drug cis-dichlorodiammineplatinum(II) (cis-platinum), 9L rat brain gliosarcoma cells grown in vitro were depleted of intracellular polyamines by -difluoromethylornithine (DFMO; 10 mM, 48 hr), an enzymeactivated, irreversible inhibitor of the polyamine-synthetic enzyme ornithine decarboxylase. In contrast to studies that showed that the cytotoxicity of 1,3-bis (2-chloroethyl)-1-nitrosourea as measured by colony-forming efficiency is enhanced by DFMO depletion of intracellular polyamines, the cytotoxicity of cis-platinum was significantly decreased in polyamine-depleted 9L cells. At 10, 1, and 0.1% survival levels, the dose modification factors were 2.0 to 2.1. Addition of exogenous putrescine to polyamine-depleted 9L cells 24 hr before treatment with cis-platinum partially reversed this phenomenon. When 9L cells were treated either with DFMO and cis-platinum or with DFMO, putrescine, and cis-platinum for 1 hr, a time period that is too short for DFMO to affect intracellular polyamine levels, the cytotoxicity of cis-platinum was decreased, but to a significantly lesser extent than by the 48-hr DFMO pretreatment. Putrescine alone did not alter the cytotoxic effect of cis-platinum when administered either 24 or 1 hr before treatment. DFMO appears to affect cis-platinum cytotoxicity by two different mechanisms, the first medicated through polyamine depletion and the second through a direct interaction with cis-platinum.

¹ Supported by American Cancer Society Grant RD-137, NIH Grant CA-13525 and the Morris Stulsaft Foundation.

² Recipient of travel grants from the Swedish Natural Science Research Council (R-RA 4685-100) and the Swedish Medical Research Council (B 81-04R-6065-504106065). Visiting predoctoral fellow at the Brain Tumor Research Center.

³ To whom requests for reprints should be addressed, at Brain Tumor Research Center, 783 HSW, University of California, San Francisco, Calif., 94143.

Received 11/ 2/81. Accepted 1/13/82.

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