Description
Glycinamide ribonucleotide formyltransferase (GART) is a folate-dependent enzyme required for de novo purine synthesis. Lometrexol is a folate analog antimetabolite with antineoplastic activity. At nanomolar conentrations, it inhibits GART preventing de novo purine synthesis, inhibiting DNA synthesis, arresting cells in the S phase of the cell cycle, and inhibiting tumor cell proliferation.
Uses
It is an antifolate which inhibits glycinamide ribonucleotide formyltransferase (GARFT), an enzyme essential for de novo purine synthesis.
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.
References
[1] G P BEARDSLEY. A new folate antimetabolite, 5,10-dideaza-5,6,7,8-tetrahydrofolate is a potent inhibitor of de novo purine synthesis.[J]. The Journal of Biological Chemistry, 1989, 264 1: 328-333.
[2] G PIZZORNO. (6R)-5,10-Dideaza-5,6,7,8-tetrahydrofolic acid effects on nucleotide metabolism in CCRF-CEM human T-lymphoblast leukemia cells.[J]. Cancer research, 1991, 51 9: 2291-2295.
[3] JULIE L BRONDER Richard G M. Antifolates targeting purine synthesis allow entry of tumor cells into S phase regardless of p53 function.[J]. Cancer research, 2002, 62 18: 5236-5241.
