A comparison of the effects of nine folate analogs on early and late murine hematopoietic progenitor cells in vitro

Pur pose: Since the clinical introduction of the antifolates aminopterin (A MT) and methotrexate (MTX) many promising analogs have been developed. A co mmon feature of these compounds is their ability to induce bone marrow; sup pression. However, few studies have been undertaken on the effect of the fo lic acid analogs on the cells comprising the hematopoietic system. Methods: In this paper we describe the effects of the novel thymidylate synthase (T S) inhibitors raltitrexed (Tomudex, ZD1694), AG337 (nolatrexed, Thymitaq), and the two closely related analogs 5,8-dideazaisofolic acid (IAHQ2a) and 2 -desamino-2-methyl 5,8-dideazaisofolic acid (IAHQ2c), the glycinamide-ribon ucleosyl (GAR) transformylase inhibitor lometrexol (DDATHF), and the dihydr ofolate reductase (DHFR) inhibitors MTX, AMT, trimetrexate (TMTX), and edat rexate (EDX) on purified populations of early and late murine hematopoietic progenitor cells. Results/Conclusion: All the antifolates inhibited bone m arrow proliferation in suspension cultures and all drugs except DDATHF inhi bited colony formation by more mature progenitor cells (CFU-C) in clonogeni c assays. The lipophilic agents TMTX and AG337 were most toxic, totally abo lishing CFU-C colony formation at high concentrations. When IAHQ2c, raltitr exed, DDATHF, and MTX were investigated further for effects on the immature high proliferative potential colony-forming cells (HPP-CFCs) in semisolid and limiting dilution cultures, none of these agents were found to be toxic to the HPP-CFC. but induced a reversible developmental arrest in the proge nitor cell population.