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Cell Cycle Age Response of 9L Cells to 1,3-Bis(2-chloroethyl)-1-nitrosourea and Modification by -Difluoromethylornithine¹

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

We have determined the cell cycle age response of 9L rat brain tumor cells to 1,3-bis(2-chloroethyl)-1-nitrosourea using centrifugal elutriation to obtain populations of cells enriched in G₁, S, and G₂-M phases. While cells in all phases of the cell cycle were killed by 20 or 40 µM 1,3-bis(2-chloroethyl)-1-nitrosourea, cells in G₁ and G₂-M phases were more sensitive than cells in S phase. The differential sensitivity was more pronounced at the higher dose, which will markedly alter the distribution of cells through the cell cycle. In a clinical setting, this factor could affect the efficacy of either fractionated or multimodality protocols. Treatment with -difluoromethylornithine, a polyamine biosynthesis inhibitor, potentiated the cytotoxic effects of 20 µM 1,3-bis(2-chloroethyl)-1-nitrosourea against G₁- and G₂-M- but not against S-phase cells; however, at a higher dose of 1,3-bis(2-chloroethyl)-1-nitrosourea (40 µM), the cytotoxicity was potentiated for cells in all phases of the cell cycle. In -difluoromethylornithine-treated cells, the phenomenon could be reversed by adding 1 mM putrescine 24 hr before treatment with 1,3-bis(2-chloroethyl)-1-nitrosourea. Therefore, the potentiation of 1,3-bis(2-chloroethyl)-1-nitrosourea cytotoxicity appears to be related to polyamine depletion.

¹ Supported by ACS Grant RD-137, NIH Grants CA-13525 and CA-31867, 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 (B81-04R-6065-504106065).

³ Recipient of a travel grant from the Swedish Natural Science Research Council (R-RA 4818-100).

⁴ To whom requests for reprints should be addressed at the Brain Tumor Research Center, University of California, San Francisco, Calif. 94143.

Received 5/ 3/82. Accepted 12/16/82.