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Drug-interaction studies evaluating T-cell proliferation reveal distinct activity of dasatinib and imatinib in combination with cyclosporine A

Citation

Blake, SJ and Hughes, TP and Lyons, AB, Drug-interaction studies evaluating T-cell proliferation reveal distinct activity of dasatinib and imatinib in combination with cyclosporine A, Experimental Hematology, 40, (8) pp. 612 - 621. ISSN 0301-472X (2012) [Refereed Article]

Copyright Statement

Copyright 2012 ISEH - Society for Hematology and Stem Cells

DOI: doi:10.1016/j.exphem.2012.04.003

Abstract

Development of small molecule tyrosine kinase inhibitors for the treatment of chronic myeloid leukemia has been astonishingly successful; however, their off-target effects have generated both challenges and opportunities for extending their clinical application. Dasatinib and imatinib are two of the most commonly used tyrosine kinase inhibitors and both have been shown to impact T-cell function. Due to this activity, their use as potential immune suppressants has been proposed. In this report, we investigated drug interactions with cyclosporine A in suppressing T-cell proliferation. Dasatinib and imatinib were titrated against varying concentrations of cyclosporine in the cultures and T-cell proliferation assessed by 5-6-carboxyfluorescein diacetate, succinimidyl ester dye dilution. These proliferation data were then used to determine the combination index to evaluate additive, synergistic, or antagonistic interactions between the drugs. This analysis uncovered a number of different drug interactions affecting T-cell proliferation. Cyclosporine had an additive or synergistic effect on T-cell proliferation when combined with dasatinib and imatinib for 3 of the 4 methods of stimulating T-cell proliferation. However, when T cells were stimulated with anti-CD3 and anti-CD28 antibodies, this interaction was found to be strongly antagonistic at low dasatinib concentrations. In contrast, this strong antagonism was not observed when imatinib was used in combination with cyclosporine A. This study suggests drug interactions affecting T cells may need to be carefully taken into account when using tyrosine kinase inhibitors. Furthermore, the technique to evaluate drug interactions is novel, and applicable to study any interaction affecting proliferation

Item Details

Item Type:Refereed Article
Keywords:T lymphocytes, dasatinib, imatinib, cyclosporine
Research Division:Medical and Health Sciences
Research Group:Immunology
Research Field:Cellular Immunology
Objective Division:Health
Objective Group:Clinical Health (Organs, Diseases and Abnormal Conditions)
Objective Field:Immune System and Allergy
Author:Lyons, AB (Dr Bruce Lyons)
ID Code:82337
Year Published:2012
Web of Science® Times Cited:8
Deposited By:Medicine (Discipline)
Deposited On:2013-01-25
Last Modified:2013-05-07
Downloads:0

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