The reversal of methotrexate cytotoxicity to mouse bone marrow cells by leucovorin and nucleosides

H. M. Pinedo, D. S. Zaharko, J. M. Bull, B. A. Chabner

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145 Scopus citations


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 10-8M 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 10-7M MTX was completely reversed by equimolar concentrations of leucovorin, but with higher MTX concentrations, relatively more leucovorin was required. While 10-5M MTX was rescued by 10-3M leucovorin, rescue of the toxic effect of 10-4M MTX by 10-3M leucovorin was not observed. In contrast to the rescue by leucovorin, toxicity of all MTX concentrations up to 10-4M was completely prevented by 10-5M thymidine with 10-5M adenosine, inosine, or hypoxanthine. Single nucleosides or thymidine with guanosine were ineffective, as were lower concentrations (≤10-6M) 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.

Original languageEnglish (US)
Pages (from-to)4418-4424
Number of pages7
JournalCancer Research
Issue number12
StatePublished - 1976
Externally publishedYes

ASJC Scopus subject areas

  • Cancer Research
  • Oncology


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