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|Title:||Dasatinib targets chronic myeloid leukemia-CD34⁺ progenitors as effectively as it targets mature cells|
|Other Titles:||Dasatinib targets chronic myeloid leukemia-CD34(+) progenitors as effectively as it targets mature cells|
|Citation:||Haematologica, 2013; 98(6):896-900|
|Publisher:||Ferrata Storti Foundation|
|Devendra K. Hiwase, Verity A. Saunders, Eva Nievergall, Douglas D. Ross, Deborah L. White, and Timothy P. Hughes|
|Abstract:||Dasatinib is effective in most chronic phase chronic myeloid leukemia patients both in first-line therapy and following imatinib failure. While imatinib uptake into CD34(+) cells is low compared to mononuclear cells, few data evaluate how well dasatinib targets primitive CML cells. This study compares intracellular concentration of dasatinib and Bcr-Abl kinase inhibition in CML-CD34(+) progenitors and mononuclear cells induced by dasatinib. The intracellular concentrations of dasatinib were similar between CML-CD34(+) and mononuclear cells (P=0.8). Similarly, there was no significant difference in the degree of dasatinib-mediated Bcr-Abl kinase inhibition. ABCB1 (MDR1) and ABCG2 inhibitors neither increased dasatinib intracellular concentration nor enhanced dasatinib-mediated Bcr-Abl kinase inhibition. In contrast to nilotinib, we show that dasatinib is not an ABCB1 inhibitor. Thus, dasatinib targets CML-CD34(+) progenitors as effectively as it targets mononuclear cells. ABCB1 and ABCG2 efflux pumps do not appear to influence the intracellular dasatinib concentration in CML-CD34(+) progenitors.|
|Keywords:||Leukocytes, Mononuclear; Cells, Cultured; Humans; Pyrimidines; Thiazoles; ATP-Binding Cassette Transporters; Neoplasm Proteins; Fusion Proteins, bcr-abl; Antineoplastic Agents; Antigens, CD34; Protein Kinase Inhibitors; Substrate Specificity; Neoplastic Stem Cells; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Dasatinib; ATP Binding Cassette Transporter, Sub-Family G, Member 2; ATP Binding Cassette Transporter, Sub-Family B; ATP-Binding Cassette, Sub-Family B, Member 1|
|Rights:||©2013 Ferrata Storti Foundation|
|Appears in Collections:||Medicine publications|
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