Abstract 2426: <i>In vitro</i> and <i>in vivo</i> evaluation of dasatinib and imatinib on physiological parameters of pulmonary arterial hypertension .
Authors: Mausumee Guha, James Hennan, Julia Li, Damir Simic, Jochen Woiche, Bethany Baumgart, Thomas Sanderson, Michael Graziano, Roderick Bunch
Journal: Cancer Research (2013)

Abstract Pulmonary arterial hypertension (PAH), defined by increase in mean pulmonary arterial pressure (PAP), results from occlusion or vasoconstriction of the pulmonary veins and can lead to progressive right ventricular failure. The tyrosine kinase inhibitor (TKI) imatinib, indicated for chronic myelogenous leukemia (CML) is being investigated as a potential treatment for PAH, due to its anti-vasoproliferative properties. However, the TKI dasatinib also used for CML is associated with PAH in a small percentage of heavily pre-treated patients although partial or complete reversibility is seen after discontinuation of treatment. Despite the different kinase profiles, studies in rat models of PAH have shown that both TKIs are equally efficacious in reversing functional and structural PAH-related changes. Therefore, nonclinical in vivo (SD rat) and in vitro (human pulmonary artery endothelial cells/smooth muscle cells [hPAEC/hPASM) studies evaluating direct effects of the two TKIs were conducted to understand the potential mechanistic differences for the apparently different clinical effect. The in vivo study explored direct effects of vehicle (80 mM citric acid; control), clinically relevant doses of imatinib and dasatinib (30 or 8 mg/kg/day, oral) and monocrotaline (single i.p. dose, 70 mg/kg; positive control) on PAH-related pulmonary changes in rats (1-month treatment). Monocrotaline reduced nitric oxide (NO; vasodilation) and increased endothelin-1 (ET-1; vasoconstriction) levels in plasma, induced structural changes (perivascular inflammation, EC injury and SMC proliferation) in PA and lungs, and increased (2-5× control) systolic and diastolic PAP and right ventricular pressure. In contrast, both imatinib and dasatinib increased NO in plasma (2.5×), did not any induce PAH-related structural changes (PA or lungs) and did not alter hemodynamic function compared to controls. The in vitro hPAEC/PASM co-culture model demonstrated that imatinib and dasatinib at clinically relevant (Cmax) concentrations increased NO and decreased ET-1 protein and mRNA. Our results demonstrate that dasatinib, as imatinib, does not have the potential to directly induce PAH-related changes in vivo or in vitro. In addition, both molecules induce biochemical changes in vivo and in vitro consistent with a protective effect on PAP. Citation Format: Mausumee Guha, James Hennan, Julia Li, Damir Simic, Jochen Woiche, Bethany Baumgart, Thomas Sanderson, Michael Graziano, Roderick Bunch. In vitro and in vivo evaluation of dasatinib and imatinib on physiological parameters of pulmonary arterial hypertension . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2426. doi:10.1158/1538-7445.AM2013-2426 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.