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Reduction in cis-Diamminedichloroplatinum(II)-induced Cytotoxicity, Sister Chromatid Exchange, and DNA Interstrand Cross-Links in 9L Cells Treated with the Polyamine Biosynthesis Inhibitor (2R,5R)-6-Heptyne-2,5-diamine¹

Brain Tumor Research Center, Department of Neurological Surgery [K. M. M., 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

The effects of depletion of intracellular levels of the polyamines putrescine and spermidine on cis-diamminedichloroplatinum(II)-induced cytotoxicity, sister chromatid exchanges, DNA interstrand cross-linking, and intracellular glutathione levels were studied in 9L rat brain tumor cells pretreated with the ornithine decarboxylase inhibitor (2R,5R)-6-heptyne-2,5-diamine (R,R-MAP). Pretreatment of 9L cells with R,R-MAP for 48 h decreased cis-diamminedichloroplatinum(II) cytotoxicity with an average dose reduction ratio of 0.55 at both the 5 and 10% survival levels; addition of putrescine partially prevented this effect. The number of sister chromatid exchanges and DNA interstrand cross-links was also reduced (31 and 38%, respectively). Within 24 h of treatment with R,R-MAP, intracellular glutathione levels began to increase relative to untreated control cells and were significantly elevated in R,R-MAP-treated cells 48-72 h after addition of drug. We discuss several mechanisms by which polyamine depletion could reduce cis-diamminedichloroplatinum(II) toxicity.

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

² Present address: Department of Pathology, George Washington University, 510 Ross Hall, 2300 Eye Street N.W., Washington, DC 20037.

³ Present address: Department of Medical Protozoology, London School of Hygiene and Tropical Medicine, University of London, London, WC1E 7HT, United Kingdom.

⁴ To whom requests for reprints should be addressed, at the Department of Laboratory Medicine, Box 0134, University of California, San Francisco, CA 94143.

Received 9/20/88. Revised 4/21/89. Revised 8/31/89. Accepted 9/ 6/89.