Cell-Cycle-Dependent Pharmacology of Methotrexate in HL-60

DOI Web Site 3 Citations 58 References
  • Yamauchi Atsushi
    Pharmaceutics, Division of Clinical Pharmacy, Department of Medico-Pharmaceutical Science, Faculty of Pharmaceutical Sciences, Kyushu University
  • Ichimiya Takanobu
    Pharmaceutics, Division of Clinical Pharmacy, Department of Medico-Pharmaceutical Science, Faculty of Pharmaceutical Sciences, Kyushu University
  • Inoue Kouichi
    Pharmaceutics, Division of Clinical Pharmacy, Department of Medico-Pharmaceutical Science, Faculty of Pharmaceutical Sciences, Kyushu University
  • Taguchi Yukie
    Pharmaceutics, Division of Clinical Pharmacy, Department of Medico-Pharmaceutical Science, Faculty of Pharmaceutical Sciences, Kyushu University
  • Matsunaga Naoya
    Pharmaceutics, Division of Clinical Pharmacy, Department of Medico-Pharmaceutical Science, Faculty of Pharmaceutical Sciences, Kyushu University
  • Koyanagi Satoru
    Depertment of Biochemistry, Faculty of Pharmaceutical Sciences, Fukuoka University
  • Fukagawa Tatsuo
    PRESTO, The Japan Science and Technology Corporation (JST), National Institute of Genetics and The Graduate University for Advanced Studies
  • Aramaki Hironori
    Department of Molecular Biology, Daiichi College of Pharmaceutical Sciences
  • Higuchi Shun
    Pharmaceutics, Division of Clinical Pharmacy, Department of Medico-Pharmaceutical Science, Faculty of Pharmaceutical Sciences, Kyushu University
  • Ohdo Shigehiro
    Pharmaceutics, Division of Clinical Pharmacy, Department of Medico-Pharmaceutical Science, Faculty of Pharmaceutical Sciences, Kyushu University

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Abstract

The role of the susceptibility of cells and the pharmacokinetics of MTX on the time-dependent change of methotrexate (MTX) pharmacologic action in HL-60 (human leukemia cell) was investigated from the viewpoints of the rhythm of DNA synthesis. The highest activity of MTX was observed at the time when DNA synthesis, dihydrofolate reductase (DHFR) activity, DHFR content, and DHFR mRNA content increased and the lowest activity was observed at the time when they decreased. There were significant time-dependent changes in MTX efflux. The result corresponded to the rhythm in MTX activity. The present study suggests that the time-dependent change of MTX activity is caused by a change in the sensitivity of cells and the pharmacokinetics of the drug. Therefore, the choice of dosing time associated with cell rhythmicity may help to achieve rational chronotherapeutics, increasing therapeutic effects.<br>

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