Evidence for early recruitment of granulocyte precursors during high-dose methotrexate infusions in mice.
The effects of constant exposure to high concentrations of methotrexate in vivo on the committed stem cell (CFU-C) were studied by in vitro culture of mouse bone marrow. Bone marrow samples were obstained from animals receiving a continuous infusion, and were cultured in a methotrexate-free semisolid gel system. The effects of methotrexate infusion on the pluripotent stem cell population (CFU-S) were studied as well. Constant exposure to 10(-5) M methotrexate produced a rapid decrease in total nucleated cells per femur, reaching 35% of control at 12 hr and remaining at approximately this level throughout 48 hr of drug infusion. A decrease in the number of both CFU-C and CFU-S per femur was observed, which paralleled the drop in nucleated cells during the first 24 hr. However, in contrast to an additional drop in the number of CFU-S, an increase of CFU-C number per femur was observed from 24 to 48 hr. These data indicated a self-limited cell kill of nucleated bone marrow cells, and suggested recruitment of CFU-C from the CFU-S pool between 24 and 48 hr of infusion despite continued methotrexate infusion.
D000818:Animals; D004247:DNA / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D006098:Granulocytes / Q000166:cytology; D006410:Hematopoiesis / Q000187:drug effects*; D007962:Leukocytes / Q000166:cytology; D008297:Male; D008727:Methotrexate / Q000097:blood / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D013997:Time Factors
D004247:DNA; D008727:Methotrexate