A new mechanism of methotrexate action revealed by target screening with affinity beads.

Article Details

Citation

Uga H, Kuramori C, Ohta A, Tsuboi Y, Tanaka H, Hatakeyama M, Yamaguchi Y, Takahashi T, Kizaki M, Handa H

A new mechanism of methotrexate action revealed by target screening with affinity beads.

Mol Pharmacol. 2006 Nov;70(5):1832-9. Epub 2006 Aug 25.

PubMed ID
16936229 [ View in PubMed
]
Abstract

Methotrexate (MTX) is the anticancer and antirheumatoid drug that is believed to block nucleotide synthesis and cell cycle by inhibiting dihydrofolate reductase activity. We have developed novel affinity matrices, termed SG beads, that are easy to manipulate and are compatible with surface functionalization. Using the matrices, here we present evidence that deoxycytidine kinase (dCK), an enzyme that acts in the salvage pathway of nucleotide biosynthesis, is another target of MTX. MTX modulates dCK activity differentially depending on substrate concentrations. 1-beta-D-Arabinofuranosylcytosine (ara-C), a chemotherapy agent often used in combination with MTX, is a nucleoside analog whose incorporation into chromosome requires prior phosphorylation by dCK. We show that, remarkably, MTX enhances incorporation and cytotoxicity of ara-C through regulation of dCK activity in Burkitt's lymphoma cells. Thus, this study provides new insight into the mechanisms underlying MTX actions and demonstrates the usefulness of the SG beads.

DrugBank Data that Cites this Article

Drug Targets
DrugTargetKindOrganismPharmacological ActionActions
MethotrexateDihydrofolate reductaseProteinHumans
Yes
Inhibitor
Details