In vitro and in vivo evaluation of dasatinib and imatinib on physiological parameters of pulmonary arterial hypertension
| Autor: | Michael J. Graziano, Mausumee Guha, Julia Li, Nicola Wallis, Damir Simic, James Hennan, Bethany R. Baumgart, Jochen Woicke, Thomas P. Sanderson, Roderick T. Bunch |
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| Rok vydání: | 2016 |
| Předmět: |
Male
Cancer Research Pulmonary Circulation medicine.drug_class Hypertension Pulmonary Dasatinib Gene Expression Antineoplastic Agents 030204 cardiovascular system & hematology Pharmacology Pulmonary Artery Toxicology Nitric Oxide Tyrosine-kinase inhibitor Muscle Smooth Vascular Nitric oxide Rats Sprague-Dawley 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine In vivo hemic and lymphatic diseases medicine.artery medicine Animals Pharmacology (medical) RNA Messenger Lung Protein Kinase Inhibitors Endothelin-1 business.industry Hemodynamics Imatinib medicine.disease Rats Oncology chemistry 030220 oncology & carcinogenesis Pulmonary artery Imatinib Mesylate medicine.symptom business Vasoconstriction Chronic myelogenous leukemia medicine.drug Muscle Contraction |
| Zdroj: | Cancer chemotherapy and pharmacology. 79(4) |
| ISSN: | 1432-0843 |
| Popis: | 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. 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. 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. 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. |
| Databáze: | OpenAIRE |
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