5,10-Methenyltetrahydrofolate synthetase activity is increased in tumors and modifies the efficacy of antipurine LY309887

Methenyltetrahydrofolate synthetase (MTHFS) expression enhances folate-dependent de novo purine biosynthesis. In this study, the effect of increased MTHFS expression on the efficacy of the glycinamide ribonucleotide formyltransferase (GARFT) inhibitor LY309887 was investigated in SH-SY5Y neuroblasto...

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Bibliographic Details
Published in:Archives of biochemistry and biophysics 2009-01, Vol.481 (2), p.145-150
Main Authors: Field, Martha S., Anguera, Montserrat C., Page, Rodney, Stover, Patrick J.
Format: Article
Language:English
Subjects:
Animals
Antifolate
Antineoplastic Agents - pharmacology
Antineoplastic Agents - therapeutic use
Biopsy
Carbon-Nitrogen Ligases - drug effects
Carbon-Nitrogen Ligases - genetics
Carbon-Nitrogen Ligases - metabolism
Cats
DNA, Complementary - genetics
Dogs
Folate metabolism
Glycinamide ribonucleotide formyltransferase
Humans
LY309887
Methenyltetrahydrofolate synthetase
Mice
Mice, Transgenic
Neuroblastoma - drug therapy
Neuroblastoma - enzymology
Neuroblastoma - pathology
Purine biosynthesis
Tetrahydrofolates - pharmacology
Transplantation, Heterologous
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Summary:Methenyltetrahydrofolate synthetase (MTHFS) expression enhances folate-dependent de novo purine biosynthesis. In this study, the effect of increased MTHFS expression on the efficacy of the glycinamide ribonucleotide formyltransferase (GARFT) inhibitor LY309887 was investigated in SH-SY5Y neuroblastoma. GARFT catalyzes the incorporation of formate, in the form of 10-formyltetrahydrofolate, into the C8 position of the purine ring during de novo purine biosynthesis. SH-SY5Y neuroblastoma with increased MTHFS expression displayed a 4-fold resistance to the GARFT inhibitor LY309887, but did not exhibit resistance to the thymidylate synthase inhibitor Pemetrexed. This finding supports a mechanism whereby MTHFS increases the availability of 10-formyltetrahydrofolate for GARFT. MTHFS expression is elevated in animal tumor tissues compared to surrounding normal tissue, consistent with the dependence of transformed cells on de novo purine biosynthesis. The level of MTHFS expression in tumors may predict the efficacy of antipurine agents that target GARFT.
ISSN:0003-9861
1096-0384
DOI:10.1016/j.abb.2008.11.001