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.
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
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ATP Binding Cassette Transporter, Subfamily G, Member 2
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ATP-Binding Cassette Transporters / antagonists & inhibitors
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ATP-Binding Cassette Transporters / metabolism
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Antigens, CD34 / metabolism*
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Antineoplastic Agents / pharmacology*
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Cells, Cultured
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Dasatinib
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Fusion Proteins, bcr-abl / antagonists & inhibitors
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Humans
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism*
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Leukocytes, Mononuclear / immunology
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Leukocytes, Mononuclear / metabolism
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Neoplasm Proteins / antagonists & inhibitors
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Neoplasm Proteins / metabolism
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Neoplastic Stem Cells / drug effects*
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Neoplastic Stem Cells / metabolism*
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Protein Kinase Inhibitors / pharmacology*
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Pyrimidines / pharmacology*
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Substrate Specificity / drug effects
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Thiazoles / pharmacology*
Substances
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ABCB1 protein, human
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ABCG2 protein, human
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ATP Binding Cassette Transporter, Subfamily B
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ATP Binding Cassette Transporter, Subfamily B, Member 1
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ATP Binding Cassette Transporter, Subfamily G, Member 2
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ATP-Binding Cassette Transporters
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Antigens, CD34
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Antineoplastic Agents
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Neoplasm Proteins
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Protein Kinase Inhibitors
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Pyrimidines
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Thiazoles
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Fusion Proteins, bcr-abl
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Dasatinib