5-fluorocytosine: inhibition of hematopoiesis in vitro and reversal of inhibition by uracil.
The in vitro effect of 5-fluorocytosine on human and murine hematopoiesis was studied by means of soft-gel assays for erythroid and myeloid colony-forming cells. The drug consistently inhibited colony formation by granulocyte-monocyte and erythroid precursor cells. Clear effects were observable at concentrations of 5-fluorocytosine of 5 x 10(-5) M (6.5 micrograms/ml), and concentrations of 5 x 10(-4) M (65 micrograms/ml) caused approximately 90% inhibition of cloning of bone marrow myeloid colony-forming cells from mice and normal humans. Greater concentrations of 5-fluorocytosine were required to inhibit erythroid progenitors than to inhibit myeloid precursors. Uracil competitively reversed the toxicity of 5-fluorocytosine. Our data strongly suggest that the hematopoietic toxicity of 5-5-fluorocytosine is mediated through cellular metabolism of the drug. The reversal of mammalian, but not of fungal, cytotoxic effects of 5-fluorocytosine by uracil may have important clinical applications.
D000818:Animals; D001854:Bone Marrow Cells; D002478:Cells, Cultured; D003114:Colony-Forming Units Assay; D003596:Cytosine / Q000031:analogs & derivatives*; D003864:Depression, Chemical; D004305:Dose-Response Relationship, Drug; D005437:Flucytosine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D006098:Granulocytes / Q000187:drug effects; D006410:Hematopoiesis / Q000187:drug effects*; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008815:Mice, Inbred Strains; D009000:Monocytes / Q000187:drug effects; D014498:Uracil / Q000494:pharmacology*
D014498:Uracil; D003596:Cytosine; D005437:Flucytosine