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

Abstract

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.

Inhibitory Effect of Cell Phones Against Human Breast Cancer and Myeloid Leukemia Cells Proliferation in Culture Media

“…1 mL sample (after trypsinization for MCF-7) was taken from the plaque on the last day of the culture for control and experimental groups and this sample was used for cell count and viability. 13,14 Cell Count, Viability Test and MTT Test By taking 10 µL of the obtained cell solution, the cells were counted under the light microscope (Olympus BX51, Tokyo, Japan) using the Thoma cell counting chamber (Arat et al, 2008). Acridine Orange (Sigma, A6014, Germany) viability assay was used to measure the viability of cells.…”

Reply to Comment on low‐dose tyrosine kinase inhibitors before treatment discontinuation do not impair treatment‐free remission in chronic myeloid leukemia patients: Results of a retrospective study

“…In this case, it is quite unlikely that the plasma concentration was in the therapeutic range. Aoyama et al 8 recently observed in a K562 cell line model that the cytostatic effect (depending on intracellular accumulation) of imatinib, nilotinib, or dasatinib persists even after the disappearance of the drug in the plasma. The therapeutic effects of TKIs are primarily based on their intracellular activity, plasma concentrations being only an indirect but useful marker.…”