5-Formyltetrahydrofolate promotes the net dissociation of methotrexate bound to dihydrofolate reducÃ-ase in the Ehrlich ascites tumor (L. H. Matherly ef al., Cancer Res., 43: 26942699, 1983). Treatment of Ehrlich tumor cells with glucose or inhibitors of electron transfer stabilized the association of the antifolate with dihydrofolate reductase as reflected by a 2-fold increased fraction of dih...

The folate analog, methotrexate, binds very tightly to dihydrofolate reductase. However, free intracellular methotrexate in excess of the enzyme-binding capacity is needed to suppress cellular dihydrofolate reduction, and the effects of methotrexate are rapidly reversible if methotrexate is removed from the extracellular media. The apparent paradox may be explained on the basis of a single high...

Pteridine reductase 1 (PTR1) is a novel broad spectrum enzyme of pterin and folate metabolism in the protozoan parasite Leishmania. Overexpression of PTR1 confers methotrexate resistance to these protozoa, arising from the enzyme's ability to reduce dihydrofolate and its relative insensitivity to methotrexate. The kinetic mechanism and stereochemical course for the catalyzed reaction confirm PT...

The folate antagonists, in particular amethoptenin (methotrexate), continue to be useful drugs for the treatment of certain neoplastic diseases in man. The effectiveness of amethoptenin in preventing DNA synthesis and cellular replication appears to be a consequence of inhibition of the enzyme dihydrofolate reductase. This premise is sup ported by in vivo studies which show that in patients tre...

Previous investigations have suggested that high-dose methotrexate with leucovorin rescue is a potentially useful strategy for overcoming antifolate resistance. Interactions between methotrexate (MTX) and leu covorin and their respective metabolites appear to occur at multiple intracellular sites, including dihydrofolate reducÃ-ase(MTX/MTX polyglutamates versus dihydrofolate) and other folate-d...

Many new analogues of dihydrofolate and dihydrohomofolate have been synthesized and tested as substrates of dihydrofolate reductase. Since all of the dihydroderivatives were efficiently reduced by the action of dihydrofolate reductase from L1210 mouse leukemia cells, the tetrahydroderivatives thus formed could be tested directly for cofactor and inhibitor activity with thymidylate synthetase. A...

Streptococcus pneumoniae isolates resistant to several antimicrobial agent classes including trimethoprim-sulfamethoxazole have been reported with increasing frequency throughout the world. The MICs of trimethoprim, sulfamethoxazole, and trimethoprim-sulfamethoxazole (1:19) for 259 clinical isolates from South Africa were determined, and 166 of these 259 (64%) isolates were resistant to trimeth...

Preliminary evidence is presented that indicates that the dihydrofolate reductase activity of amethopterin-sensitive Streptococcus faecium var. durans ATCC 8043 is separable into two dihydrofolate reductases, one of which also reduces folate.

Previous studies from this laboratory have shown that the addition of leucovorin to tumor cells dissociates methotrexate, but not methotrexate polyglutamates, from dihydrofolate reductase (L. H. Matherly, D. W. Fry, and I. D. Goldman, Cancer Res., 43: 2694-2699, 1983). To further assess the importance of these interactions to leucovorin rescue, antifolate growth inhibition toward L1210 cells in...