title: In vitro and in vivo evaluation of dasatinib and imatinib on physiological parameters of pulmonary arterial hypertension.
abstract: 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.
authors.affiliation: Bristol-Myers Squibb Pharmaceutical Company, 777 Scudders Mill Road, Princeton, NJ, 08536, USA. bethany.baumgart@bms.com.
authors.forename: Bethany
authors.initials: B
authors.lastname: Baumgart
authors.affiliation: Bristol-Myers Squibb Pharmaceutical Company, 777 Scudders Mill Road, Princeton, NJ, 08536, USA.
authors.forename: Mausumee
authors.initials: M
authors.lastname: Guha
authors.affiliation: Bristol-Myers Squibb Pharmaceutical Company, 777 Scudders Mill Road, Princeton, NJ, 08536, USA.
authors.forename: James
authors.initials: J
authors.lastname: Hennan
authors.affiliation: Bristol-Myers Squibb Pharmaceutical Company, 777 Scudders Mill Road, Princeton, NJ, 08536, USA.
authors.forename: Julia
authors.initials: J
authors.lastname: Li
authors.affiliation: Bristol-Myers Squibb Pharmaceutical Company, 777 Scudders Mill Road, Princeton, NJ, 08536, USA.
authors.forename: Jochen
authors.initials: J
authors.lastname: Woicke
authors.affiliation: Bristol-Myers Squibb Pharmaceutical Company, 777 Scudders Mill Road, Princeton, NJ, 08536, USA.
authors.forename: Damir
authors.initials: D
authors.lastname: Simic
authors.affiliation: Bristol-Myers Squibb Pharmaceutical Company, 777 Scudders Mill Road, Princeton, NJ, 08536, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Graziano
authors.affiliation: Bristol-Myers Squibb Pharmaceutical Company, 777 Scudders Mill Road, Princeton, NJ, 08536, USA.
authors.forename: Nicola
authors.initials: N
authors.lastname: Wallis
authors.affiliation: Bristol-Myers Squibb Pharmaceutical Company, 777 Scudders Mill Road, Princeton, NJ, 08536, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Sanderson
authors.affiliation: Bristol-Myers Squibb Pharmaceutical Company, 777 Scudders Mill Road, Princeton, NJ, 08536, USA.
authors.forename: Roderick Todd
authors.initials: RT
authors.lastname: Bunch
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000633:toxicity*; D000069439:Dasatinib / Q000493:pharmacokinetics / Q000633:toxicity*; D019332:Endothelin-1 / Q000097:blood; D015870:Gene Expression / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000139:chemically induced* / Q000503:physiopathology; D000068877:Imatinib Mesylate / Q000493:pharmacokinetics / Q000633:toxicity*; D008168:Lung / Q000473:pathology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009569:Nitric Oxide / Q000097:blood; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics / Q000633:toxicity*; D011651:Pulmonary Artery / Q000187:drug effects; D011652:Pulmonary Circulation / Q000187:drug effects; D012333:RNA, Messenger / Q000097:blood; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000970:Antineoplastic Agents; D019332:Endothelin-1; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D009569:Nitric Oxide; D000068877:Imatinib Mesylate; D000069439:Dasatinib
keywords: Dasatinib; Imatinib; Nonclinical; Pulmonary arterial hypertension