Continuous Cytostatic Effects of BCR-ABL Tyrosine Kinase Inhibitors (TKIs) after Washout in Human Leukemic K562 Cells

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  • Aoyama Tsuyoshi
    Laboratory of Pharmacokinetics, Faculty of Pharmaceutical Sciences, Hokkaido University
  • Shibayama Yoshihiko
    Department of Drug Fomulation, Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido
  • Furukawa Tatsuhiko
    Department of Molecular Oncology, Graduate School Medical and Dental Sciences, Kagoshima University
  • Sugawara Mitsuru
    Laboratory of Pharmacokinetics, Faculty of Pharmaceutical Sciences, Hokkaido University
  • Takekuma Yoh
    Laboratory of Pharmacokinetics, Faculty of Pharmaceutical Sciences, Hokkaido University

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Abstract

<p>Tyrosine kinase inhibitors (TKIs) are used as the first choice for chronic myeloid leukemia (CML) pharmacotherapeutics. Some patients taking these drugs showed good therapeutic reactivity despite the disappearance of drugs from blood. We investigated whether these drugs have sustained effects even after their disappearance and whether their effects depend on their amounts of intracellular accumulation. Cell proliferation after exposure of K562 cells or Multidrug resistance-1 (MDR-1)-transfected K562 cells was determined by a cell counting kit-8 assay. The intracellular accumulation amount of the drug showing a sustained cytostatic effect was measured by ultra high performance liquid chromatography mass spectrometry. Cell viability decreased in a culture time-dependent manner after washing out nilotinib and dasatinib. The sustained cytostatic effect of dasatinib, but not that of nilotinib, correlated with the intracellular accumulation level. In contrast, imatinib showed continuous a cytostatic effect after drug washout for long-term exposure but not after drug washout for short-term exposure. These results suggest that a good response in patients with a low serum concentration of imatinib, nilotinib or dasatinib may be due to the cytostatic effect of that drug continues even after its disappearance in plasma.</p>

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