Lometrexol hydrate was used to compare the biological activity of potent inhibitor of human GARFTase.[1]
Biochem/physiol Actions
Glycinamide Ribonucleotide Formyltransferase (GARFTase) is a folate-dependent enzyme required for de novo purine synthesis. Lometrexate is a potent inhibitor of GARFTase, but does not interfere with enzymes involved in the synthesis of folate. Lometrexerol has been tested clinically for the treatment of various cancers as an anti-folate like agent, similar to methotrexate. Treatment with lometrexol rapidly decreases ATP and GTP levels, cell cycle arrest and induces apoptosis. Although depletion of nucleotide pools induces p53 expression, lometrexol is cytotoxic in both wild-type and mutant p53 expressing tumor cells. Lometrexol is cytotoxic in CCRF-CEm leukemia cells with an IC50 of 2.9 nM.
Seminars in oncology, 26(2 Suppl 6), 74-81 (1999-12-22)
Antifolate drugs, as a class, have broad-spectrum activity against both hematologic and solid human malignancies. The pharmacokinetics of the classical antifolate methotrexate have been well-defined and pharmacokinetic data can be exploited to reduce the toxicity and enhance the activity of
Journal of medicinal chemistry, 41(18), 3539-3545 (1998-08-28)
The 4-amino-7-oxo-substituted analogues of 5-deaza-5,6,7, 8-tetrahydrofolic acid (5-DATHF) and 5,10-dideaza-5,6,7, 8-tetrahydrofolic acid (DDATHF) were synthesized as potential antifolates. Treatment of the alpha,beta-unsaturated esters 11a-c, obtained in one synthetic step from commercially available para-substituted methyl benzoates (9a-c) and methyl 2-(bromomethyl)acrylate (10)
Clinical cancer research : an official journal of the American Association for Cancer Research, 6(8), 3304-3311 (2000-08-24)
A murine leukemia cell line was identified that is highly resistant to methotrexate (MTX), due to impaired transport, but fully sensitive to 5,10-dideazatetrahydrofolate (DDATHF). A valine-to-methionine substitution at amino acid 104 in the reduced folate carrier (RFC1) explains this disparity
The Journal of biological chemistry, 275(34), 26599-26606 (2000-06-17)
Four L1210 murine leukemia cell lines resistant to 5, 10-dideazatetrahydrofolate (DDATHF) and other folate analogs, but sensitive to continuous exposure to methotrexate, were developed by chemical mutagenesis followed by DDATHF selective pressure. Endogenous folate pools were modestly reduced but polyglutamate
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