Cell-cycle-dependent pharmacology of methotrexate in HL-60.
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.
Yamauchi
Atsushi
A
Pharmaceutics, Division of Clinical Pharmacy, Department of Medico-Pharmaceutical Science, Faculty of Pharmaceutical Sciences, Kyushu University, Japan.
Ichimiya
Takanobu
T
Inoue
Kouichi
K
Taguchi
Yukie
Y
Matsunaga
Naoya
N
Koyanagi
Satoru
S
Fukagawa
Tatsuo
T
Aramaki
Hironori
H
Higuchi
Shun
S
Ohdo
Shigehiro
S
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D015152:Blotting, Northern; D002453:Cell Cycle / Q000502:physiology*; D049109:Cell Proliferation / Q000187:drug effects; D005493:Folic Acid Antagonists / Q000493:pharmacokinetics / Q000494:pharmacology*; D018922:HL-60 Cells; D006801:Humans; D008727:Methotrexate / Q000493:pharmacokinetics / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis; D012334:RNA, Neoplasm / Q000096:biosynthesis; D013762:Tetrahydrofolate Dehydrogenase / Q000378:metabolism; D013936:Thymidine / Q000378:metabolism
D000964:Antimetabolites, Antineoplastic; D005493:Folic Acid Antagonists; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D013762:Tetrahydrofolate Dehydrogenase; D013936:Thymidine; D008727:Methotrexate