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First published on August 25, 2006; DOI: 10.1124/mol.106.025866

0026-895X/06/7005-1832-1839$20.00
Mol Pharmacol 70:1832-1839, 2006

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A New Mechanism of Methotrexate Action Revealed by Target Screening with Affinity Beads

Hitoshi Uga, Chikanori Kuramori, Akiko Ohta, Yasunori Tsuboi, Hiroshi Tanaka, Mamoru Hatakeyama, Yuki Yamaguchi, Takashi Takahashi, Masahiro Kizaki, and Hiroshi Handa

Aphoenix Inc., Tokyo, Japan (H.U., A.O., Y.T.); Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama, Japan (C.K., M.H., Y.Y., H.H.); Graduate School of Science and Engineering, Department of Applied Chemistry, Tokyo Institute of Technology, Tokyo, Japan (H.T., T.T.); and Division of Hematology, Keio University School of Medicine, Tokyo, Japan (M.K.)

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.

Received for publication April 26, 2006.

Accepted for publication August 25, 2006.

Address correspondence to: Dr. Hiroshi Handa, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, 4259 Nagatsuta, Yokohama 226-8501, Japan. E-mail: hhanda{at}bio.titech.ac.jp




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[Abstract] [Full Text] [PDF]


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