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Medicine Branch [H. M. P., J. B.] and Laboratory of Chemical Pharmacology [D. S. Z., B. A. C.], National Cancer Institute, NIH, Bethesda, Maryland 20014, and Oncology Unit, Department of Internal Medicine, University Hospital, Utrecht, The Netherlands [H. M. P.]
The cytotoxic effect of methotrexate (MTX) for mouse bone marrow cells has been studied by in vitro culture of the granulocyte precursor cell (CFU-C) in a medium containing dialyzed fetal calf serum and dialyzed L-cell supernatant. The formation of 50-cell colonies was inhibited to 50% of control by 10-8 M MTX. Further increases in MTX concentration rapidly abolished colony formation by CFU-C. The potential of leucovorin and nucleosides to rescue the CFU-C from MTX toxicity was studied. Toxicity of 10-7 M MTX was completely reversed by equimolar concentrations of leucovorin, but with higher MTX concentrations, relatively more leucovorin was required. While 10-5 M MTX was rescued by 10-3 M leucovorin, rescue of the toxic effect of 10-4 M MTX by 10-3 M leucovorin was not observed. In contrast to the rescue by leucovorin, toxicity of all MTX concentrations up to 10-4 M was completely prevented by 10-5 M thymidine with 10-5 M adenosine, inosine, or hypoxanthine. Single nucleosides or thymidine with guanosine were ineffective, as were lower concentrations (
10-6 M) of the effective combinations. Thus, while leucovorin reversed the MTX toxicity to CFU-C competitively, rescue by nucleosides was noncompetitive. The significance and possible usefulness of these findings for chemotherapeutic protocols are discussed.
1 Present address: Oncology Unit, Department of Internal Medicine, University Hospital, Utrecht, The Netherlands.
2 To whom requests for reprints should be addressed.
Received 8/10/76. Accepted 8/16/76.
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