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Cytokinetic and Cytotoxic Effects of Antimetabolites on 9L Rat Brain Tumor Cells in Vitro¹

Brain Tumor Research Center of the Department of Neurological Surgery, School of Medicine, University of California, San Francisco, California 94143

Treatment of exponentially growing 9L monolayer cells with graded concentrations of methotrexate or 5-fluorouracil (5-FUra) resulted in approximately 95% cell kill, corresponding to the percentage of cells in this system labeled by autoradiography (98%). Additional cell kill could be obtained if 5-FUra was administered at a high concentration (7.7 x 10^–4 M) and could be partly reversed in the presence of 8.2 x 10^–5 M uridine.

When cell kill was measured as a function of time of exposure, a 3-hr exposure to 2.2 x 10^–4 M methotrexate or 7.7 x 10^–6 or 7.7 x 10^–4 M 5-FUra killed 30 to 50% of the cell population, which is equivalent to the percentage of the S-phase cells of the system. With both agents, additional cell kill was offset by division of unaffected G₂ cells and a drug-induced block of G₁ cells at the G₁-S border, and it depended on long drug exposure.

Nontoxic concentrations of 5-FUra could synchronize and increase the fraction of cells in the drug-sensitive S phase.

¹ This research was supported by NIH Grants CA-13525 and CA-19992 and a grant from the Deutsche Forschungsgemeinschaft.

² Research Fellow at the Brain Tumor Research Center. Permanent address: Department of Neuropathology, University of Duesseldorf, 4000 Duesseldorf, West Germany.

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

Received 9/ 4/80. Accepted 7/ 1/81.