title: The reversal of methotrexate cytotoxicity to mouse bone marrow cells by leucovorin and nucleosides.
abstract: The cytotoxic effect of methotrexate (MTX) for mouse bone marrow cells has been studied by in vitro 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 (less than or equal to 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.
mesh_terms: D000241:Adenosine / Q000494:pharmacology; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D003470:Culture Media; D006098:Granulocytes / Q000187:drug effects*; D006151:Guanosine / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D007288:Inosine / Q000494:pharmacology; D002955:Leucovorin / Q000494:pharmacology*; D007962:Leukocytes / Q000187:drug effects*; D008297:Male; D008727:Methotrexate / Q000494:pharmacology / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D012263:Ribonucleosides / Q000494:pharmacology*; D013936:Thymidine / Q000494:pharmacology
chemical_list: D003470:Culture Media; D012263:Ribonucleosides; D006151:Guanosine; D007288:Inosine; D000241:Adenosine; D002955:Leucovorin; D013936:Thymidine; D008727:Methotrexate