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LY231514, a pyrrolo[2,3-d]pyrimidine-based antifolate that inhibits multiple folate-requiring enzymes.
TLDR
The data suggest that LY231514 is a novel classical antifolate, the antitumor activity of which may result from simultaneous and multiple inhibition of several key folate-requiring enzymes via its polyglutamated metabolites. Expand
A new folate antimetabolite, 5,10-dideaza-5,6,7,8-tetrahydrofolate is a potent inhibitor of de novo purine synthesis.
TLDR
5,10-Dideazatetrahydrofolate was found to deplete cellular ATP and GTP over the same concentrations as those inhibitory to leukemic cell growth, suggesting that the locus of DDATHF action was in the de novo purine biosynthesis pathway. Expand
Impaired polyglutamylation of methotrexate as a cause of resistance in CCRF-CEM cells after short-term, high-dose treatment with this drug.
TLDR
This is the first example of a cell line which displays resistance which is solely attributable to defective methotrexate polyglutamate synthesis, and the development of resistance to metotrexate was associated with a marked decrease in the intracellular level of methotRexate polyGLutamates. Expand
Intracellular metabolism of 5,10-dideazatetrahydrofolic acid in human leukemia cell lines.
TLDR
Results suggest that polyglutamylation of (6R)-DDATHF not only represents a mechanism for trapping the drug inside the cells but also produces a more potent inhibitor of the target enzyme. Expand
Structure and functional relationships in human pur H.
TLDR
The human pur H (ATIC) gene encoding a bifunctional protein, hPurH, which carries the penultimate and final enzymatic activities of the purine nucleotide synthesis pathway, AICARFT & IMPCH, has been cloned and sequenced and the crystal structure has permitted identification of a number of candidate amino acid residues likely to be involved in catalysis and/or substrate binding. Expand
2,4-diamino-5-methyl-6-[(3,4,5-trimethoxyanilino)methyl]quinazoline (tmq), a potent non-classical folate antagonist inhibitor--I effect on dihydrofolate reductase and growth of rodent tumors in vitro
TLDR
The results of these studies encourage further evaluation of these compounds, in particular compound 14, as possible anti-neoplastic agents in the treatment of human disease. Expand
Regulation of thymidylate synthetase in mouse leukemia cells (L1210).
TLDR
Results of isotope-dilution analysis of the release of tritium from [5-3H]deoxyuridine in the intact cells indicated that thymidine added to the medium caused strong inhibition of thymidylate synthetase, the most likely limiting step in this pathway. Expand
Cytotoxicity of floxuridine and 5-fluorouracil in human T-lymphoblast leukemia cells: enhancement by leucovorin.
TLDR
The results are consistent with the hypothesis that the mechanism by which LV potentiates fluoropyrimidine cytotoxicity is the enhancement of complex formation between thymidylate synthase and 5-fluorodeoxyuridylates, presumably as a consequence of an increase of intracellular levels of 5,10-methylenetetrahydrofolate generated from LV. Expand
5,10-Dideazatetrahydrofolic acid (DDATHF) transport in CCRF-CEM and MA104 cell lines.
TLDR
The results suggest strongly that DDATHF and MTX share a common influx mechanism through the reduced folate transport system, and that bothDDATHF isomers are actively intracellularly concentrated through this route and are also rapidly converted to high chain length polyglutamates. Expand
Molecular and karyological analysis of methotrexate-resistant and -sensitive human leukemic CCRF-CEM cells.
TLDR
The development of resistance to methotrexate (75-fold) was associated with a 20-fold increase of dihydrofolate reductase activity, and an elongated marker chromosome containing a homogeneous staining region not present in the parent line was revealed. Expand
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