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Molecular Pharmacology

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Research ArticleArticle

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
Molecular Pharmacology November 2006, 70 (5) 1832-1839; DOI: https://doi.org/10.1124/mol.106.025866
Hitoshi Uga
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Chikanori Kuramori
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Akiko Ohta
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Yasunori Tsuboi
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Hiroshi Tanaka
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Mamoru Hatakeyama
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Yuki Yamaguchi
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Takashi Takahashi
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Masahiro Kizaki
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Hiroshi Handa
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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-β-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.

Footnotes

  • This work was supported in part by Grant for Research and Development Projects in Cooperation with Academic Institutions from the New Energy and Industrial Technology Development Organization.

  • ABBREVIATIONS: E3330, (2E)-3-(5-(2,3-dimethoxy-6-methyl-1,4-benzoquinoyl))-2-nonyl-2-propenoic acid; dCK, deoxycytidine kinase; DHFR, dihydrofolate reductase; ara-C, 1-β-d-arabinofuranosylcytosine; DMF, N,N-dimethylformamide; PAGE, polyacrylamide gel electrophoresis; His-dCK, polyhistidine-tagged deoxycytidine kinase; LDH, lactate dehydrogenase; MTX, methotrexate; Hx, hypoxanthine; Thd, thymidine; dCyd, deoxycytidine; CALGB-9251, Cancer and Leukemia Group B protocol 9251.

    • Received April 26, 2006.
    • Accepted August 25, 2006.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 70 (5)
Molecular Pharmacology
Vol. 70, Issue 5
1 Nov 2006
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Research ArticleArticle

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
Molecular Pharmacology November 1, 2006, 70 (5) 1832-1839; DOI: https://doi.org/10.1124/mol.106.025866

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Research ArticleArticle

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
Molecular Pharmacology November 1, 2006, 70 (5) 1832-1839; DOI: https://doi.org/10.1124/mol.106.025866
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