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

Abstract

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.

• Authors: Martha S Field, Montserrat C Anguera, Rodney Page, Patrick J Stover
• Journal: Archives of biochemistry and biophysics (Arch Biochem Biophys) Vol. 481 Issue 2 Pg. 145-50 (Jan 15 2009) ISSN: 1096-0384 [Electronic] United States
• PMID: 19022216 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• 6R-2',5'-thienyl-5,10-dideazatetrahydrofolic acid
• Antineoplastic Agents
• DNA, Complementary
• Tetrahydrofolates
• Carbon-Nitrogen Ligases
• 5,10-methenyltetrahydrofolate synthetase

Topics

• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Biopsy
• Carbon-Nitrogen Ligases (drug effects, genetics, metabolism)
• Cats
• DNA, Complementary (genetics)
• Dogs
• Humans
• Mice
• Mice, Transgenic
• Neuroblastoma (drug therapy, enzymology, pathology)
• Tetrahydrofolates (pharmacology)
• Transplantation, Heterologous