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Cancer Chemotherapy and Pharmacology
Published in: Cancer Chemotherapy and Pharmacology 4/2017

01-04-2017 | Original Article

In vitro and in vivo evaluation of dasatinib and imatinib on physiological parameters of pulmonary arterial hypertension

Authors: Bethany Baumgart, Mausumee Guha, James Hennan, Julia Li, Jochen Woicke, Damir Simic, Michael Graziano, Nicola Wallis, Thomas Sanderson, Roderick Todd Bunch

Published in: Cancer Chemotherapy and Pharmacology | Issue 4/2017

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Abstract

Purpose

Pulmonary arterial hypertension (PAH) results from occlusion or vasoconstriction of pulmonary vessels, leading to progressive right ventricular failure. Dasatinib, a BCR-ABL1 tyrosine kinase inhibitor (TKI) approved for the treatment of chronic myelogenous leukemia, has been associated with PAH. In contrast, the BCR-ABL1 TKI imatinib has demonstrated anti-vasoproliferative properties and has been investigated as a potential treatment for PAH. Here we describe studies evaluating the effects of dasatinib and imatinib on cardiovascular and pulmonary functions to understand the reported differential consequences of the two TKIs in a clinical setting.

Methods

The direct effects of dasatinib and imatinib were explored in vivo to investigate possible mechanisms of dasatinib-induced PAH. In addition, effects of dasatinib and imatinib on PAH-related mediators were evaluated in vitro.

Results

In rats, both TKIs increased plasma nitric oxide (NO), did not induce PAH-related structural or molecular changes in PA or lungs, and did not alter hemodynamic lung function compared with positive controls. Similarly, in the pulmonary artery endothelial cells and smooth muscle cells co-culture model, imatinib and dasatinib increased NO and decreased endothelin-1 protein and mRNA.

Conclusions

The results of these studies indicated that dasatinib did not induce physiological changes or molecular signatures consistent with PAH when compared to positive controls. Instead, dasatinib induced changes consistent with imatinib. Both dasatinib and imatinib induced biochemical and structural changes consistent with a protective effect for PAH. These data suggest that other factors of unclear etiology contributed to the development of PAH in patients treated with dasatinib.
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Metadata
Title
In vitro and in vivo evaluation of dasatinib and imatinib on physiological parameters of pulmonary arterial hypertension
Authors
Bethany Baumgart
Mausumee Guha
James Hennan
Julia Li
Jochen Woicke
Damir Simic
Michael Graziano
Nicola Wallis
Thomas Sanderson
Roderick Todd Bunch
Publication date
01-04-2017
Publisher
Springer Berlin Heidelberg
Published in
Cancer Chemotherapy and Pharmacology / Issue 4/2017
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI
https://doi.org/10.1007/s00280-017-3264-2

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