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|Title:||Dasatinib cellular uptake and efflux in chronic myeloid leukemia cells: therapeutic implications|
Vaz de Melo, J.
|Citation:||Clinical Cancer Research, 2008; 14(12):3881-3888|
|Publisher:||Amer Assoc Cancer Research|
|Devendra K. Hiwase, Verity Saunders, Duncan Hewett, Amity Frede, Stephanie Zrim, Phuong Dang, Laura Eadie, L. Bik To, Junia Melo, Sharad Kumar, Timothy P. Hughes and Deborah L. White|
|Abstract:||Purpose: The organic cation transporter OCT-1 mediates active transport of imatinib. We recently showed that low OCT-1 activity is a major contributor to suboptimal response in chronic myeloid leukemia (CML) patients treated with imatinib. The relevance of OCT-1 activity and efflux pumps in determining intracellular uptake and retention (IUR) of dasatinib was assessed. Experimental Design: The effect of OCT inhibitors on [14C]dasatinib and [14C]imatinib IUR was compared using peripheral blood mononuclear cells from newly diagnosed CML patients. The role of efflux transporters was studied using ABCB1- and ABCG2-overexpressing cell lines and relevant inhibitors. Results: Unlike imatinib, there was no significant difference in the dasatinib IUR at 37°C and 4°C (P = 0.8), and OCT-1 inhibitors including prazosin did not reduce dasatinib IUR significantly. In CML mononuclear cells, prazosin inhibitable IUR was significantly higher for imatinib than dasatinib (6.38 versus 1.48 ng/200,000 cells; P = 0.002; n = 11). Patients with high OCT-1 activity based on their imatinib uptake had IC50dasatinib values equivalent to patients with low OCT-1 activity. Dasatinib IUR was significantly lower in ABCB1-overexpressing cell lines compared with parental cell lines (P < 0.05). PSC833 (ABCB1 inhibitor) significantly increased the dasatinib IUR (P < 0.05) and reduced IC50dasatinib (from 100 to 8 nmol/L) in K562-DOX cell line. The ABCG2 inhibitor Ko143 significantly increased dasatinib IUR in ABCG2-overexpressing cell lines and reduced IC50dasatinib. Conclusion: Unlike imatinib, dasatinib cellular uptake is not significantly affected by OCT-1 activity, so that expression and function of OCT-1 is unlikely to affect response to dasatinib. Dasatinib is a substrate of both efflux proteins, ABCB1 and ABCG2.|
Tumor Cells, Cultured
ATP-Binding Cassette Transporters
Organic Cation Transporter 1
Fusion Proteins, bcr-abl
Drug Evaluation, Preclinical
Inhibitory Concentration 50
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
ATP Binding Cassette Transporter, Subfamily G, Member 2
ATP Binding Cassette Transporter, Subfamily B
ATP Binding Cassette Transporter, Subfamily B, Member 1
|Description:||Copyright © 2008 American Association for Cancer Research|
|Appears in Collections:||Aurora harvest 5|
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