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Time Dependence of the Potentiation of 1,3-Bis(2-chloroethyl)-1-nitrosourea Cytotoxicity Caused by -Difluoromethylornithine-induced Polyamine Depletion in 9L Rat Brain Tumor Cells¹

Brain Tumor Research Center of the Department of Neurological Surgery [L. A-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 rat brain tumor cells with 1.0 mM -difluoromethylornithine (DFMO) produced a time-dependent depletion of cellular putrescine and spermidine. An increase in the potentiation of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) cytotoxicity, measured with a colony-forming efficiency assay, followed the time course of polyamine depletion, reaching its maximum at 48 hr, the time at which maximum polyamine depletion was achieved.

Treatment with DFMO at concentrations as low as 0.05 mM for 48 hr effectively depleted putrescine and spermidine and potentiated BCNU cytotoxicity. Treatment for 96 hr with 0.01 mM DFMO produced a partial decrease in putrescine and spermidine levels and a moderate potentiation of BCNU cytotoxicity. The amount of polyamine depletion in 9L cells treated with 0.05, 0.1, and 0.5 mM DFMO was identical at both 48 and 96 hr, but potentiation of BCNU cytotoxicity was greater at 96 hr than at 48 hr.

When 9L cells were treated for 48 hr with 1 mM DFMO and DFMO was then removed from the cultures, polyamine levels did not reach control levels by 96 hr after change of medium. The potentiation of BCNU cytotoxicity during this 96-hr period correlated with the extent of polyamine depletion. When 100 µM putrescine was added to the culture medium after DFMO pretreatment (1 mM), polyamine levels approached those of control cells by 24 hr, and the amount of potentiation of DFMO cytotoxicity decreased. These results show that potentiation of BCNU cytotoxicity correlates closely with the amount of DFMO-induced polyamine depletion in 9L cells.

¹ Supported by NIH Grant CA-13525 and the Phi Beta Psi sorority.

² Recipient of a travel grant from the National Research Council for Natural Sciences (Academy of Finland).

³ To whom requests for reprints should be addressed, at Department of Laboratory Medicine, L-518, University of California, San Francisco, CA 94143.

Received 11/ 7/83. Accepted 2/ 7/84.

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