A comparison of the effects of nine folate analogs on early and late murine hematopoietic progenitor cells in vitro.
OBJECTIVE
Since the clinical introduction of the antifolates aminopterin (AMT) and methotrexate (MTX) many promising analogs have been developed. A common feature of these compounds is their ability to induce bone marrow suppression. However, few studies have been undertaken on the effect of the folic acid analogs on the cells comprising the hematopoietic system.


METHODS
In this paper we describe the effects of the novel thymidylate synthase (TS) 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-ribonucleosyl (GAR) transformylase inhibitor lometrexol (DDATHF), and the dihydrofolate reductase (DHFR) inhibitors MTX, AMT, trimetrexate (TMTX), and edatrexate (EDX) on purified populations of early and late murine hematopoietic progenitor cells.


CONCLUSIONS
All the antifolates inhibited bone marrow proliferation in suspension cultures and all drugs except DDATHF inhibited colony formation by more mature progenitor cells (CFU-C) in clonogenic assays. The lipophilic agents TMTX and AG337 were most toxic, totally abolishing CFU-C colony formation at high concentrations. When IAHQ2c, raltitrexed, 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 progenitor cell population.
Strømhaug
A
A
Section of Clinical Pharmacology, Central Laboratory, The Norwegian Radium Hospital, Oslo. astromha@klinmed.uio.no
Warren
D J
DJ
D000630:Aminopterin / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005492:Folic Acid / Q000031:analogs & derivatives*; D005493:Folic Acid Antagonists / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D008727:Methotrexate / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D011799:Quinazolines / Q000494:pharmacology; D013763:Tetrahydrofolates / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology; D016597:Trimetrexate / Q000494:pharmacology
D004791:Enzyme Inhibitors; D005493:Folic Acid Antagonists; D011799:Quinazolines; D013763:Tetrahydrofolates; D013876:Thiophenes; C067567:2-desamino-2-methyl-5,8-dideazaisofolic acid; C045894:lometrexol; D005492:Folic Acid; C068874:raltitrexed; C040210:edatrexate; D000630:Aminopterin; C099178:nolatrexed; D016597:Trimetrexate; D008727:Methotrexate