title: Inhibition of PVR with a tyrosine kinase inhibitor, dasatinib, in the swine.
abstract: OBJECTIVE
  We tested the efficacy of dasatinib, a Food and Drug Administration (FDA)-approved tyrosine kinase inhibitor, to prevent proliferative vitreoretinopathy (PVR).
  
  
  METHODS
  The effect of dasatinib on RPE sheet growth was determined by measuring enlargement of cultured RPE sheets in the presence or absence of dasatinib. Epithelial-mesenchymal transition (EMT) of RPE cells was assessed by expression of S100A4. A scratch wound assay, cell number count, and type I collagen contraction assay were used to examine the effect of dasatinib on migration, proliferation, and extracellular matrix (ECM) contraction, respectively. Our swine model of experimental PVR with green fluorescent protein-positive (GFP+) RPE cells was used to assess the efficacy of dasatinib in preventing traction retinal detachment (TRD) caused by PVR. Full-field electroretinography and histologic examination were used to determine the retinal toxicity of dasatinib.
  
  
  RESULTS
  Dasatinib prevented RPE sheet growth, cell migration, proliferation, EMT, and ECM contraction in a concentration-dependent manner. 0.1 μM dasatinib inhibited nearly 80% of vitreous fluid-stimulated collagen gel contraction. Dasatinib also prevented TRD caused by PVR in vivo. Only 1/11 eyes had a TRD in the presence of dasatinib, while all 11 controls eyes had a TRD. Dasatinib did not cause any detectable toxicity of the retina.
  
  
  CONCLUSIONS
  Dasatinib significantly inhibited PVR-related RPE changes in vitro and prevented TRD in an experimental PVR model in the swine without any detectable toxicity. Our data suggested that dasatinib may be effective in the prevention of PVR.
authors: Department of Ophthalmology and Visual Sciences, University of Louisville, Louisville, KY 40202, USA.
authors: Kazuhiko
authors: K
authors: Umazume
authors: Lanhsin
authors: L
authors: Liu
authors: Patrick A
authors: PA
authors: Scott
authors: Juan P Fernandez
authors: JP
authors: de Castro
authors: Kevin
authors: K
authors: McDonald
authors: Henry J
authors: HJ
authors: Kaplan
authors: Shigeo
authors: S
authors: Tamiya
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D000069439:Dasatinib; D004195:Disease Models, Animal; D004596:Electroretinography / Q000187:drug effects; D005260:Female; D005333:Fetus / Q000166:cytology; D011247:Pregnancy; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000633:toxicity; D011743:Pyrimidines / Q000494:pharmacology* / Q000633:toxicity; D012163:Retinal Detachment / Q000188:drug therapy / Q000517:prevention & control; D055213:Retinal Pigment Epithelium / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D013552:Swine; D013844:Thiazoles / Q000494:pharmacology* / Q000633:toxicity; D018630:Vitreoretinopathy, Proliferative / Q000188:drug therapy* / Q000517:prevention & control*; D014822:Vitreous Body / Q000166:cytology
chemical_list: D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D000069439:Dasatinib