Differential effects of the antifolates methotrexate, aminopterin and trimetrexate on murine haemopoietic progenitor cells

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Abstract
We investigated the effects of the antifolates methotrexate (MTX), aminopterin (AMT) and trimetrexate (TMTX) on murine haemopoietic progenitor cells. Colony formation by late progenitors (CFU-C) was inhibited by the antifolates and the addition of leucovorin (LV) to the cultures on day 0 or day 5 wholly or partially reversed the effects of MTX or AMT. The effect of TMTX was only effectively rescued by hypoxanthine plus thymidine (HT). In the high proliferative potential colony forming cell (HPP-CFU-C) assay the antifolates induced formation of smaller colonies, but not a reduction in absolute colony numbers. This effect was reversed by LV and indicated that the antifolates (except high TMTX concentrations) were not toxic to the HPP-CFU-C but reversibly inhibited proliferation of more mature progenitor cells. The direct effects of the drugs on HPP-CFU-C were investigated in limiting dilution assays performed with fractionated bone marrow cells. Untreated cultures contained almost only large colonies, where the addition of antifolates induced a reversible shift towards smaller colonies. The present study indicates that MTX, AMT and low TMTX concentrations are not toxic to HPP-CFU-C but that the drugs induce a developmental arrest in more mature progenitor cell populations.

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