title: Anti-angiogenic effects of the receptor tyrosine kinase inhibitor, pazopanib, on choroidal neovascularization in rats.
abstract: Neovascularization in the eye is a major cause of irreversible vision loss. The present study was undertaken to determine mechanisms through which pazopanib, a drug that targets multiple receptor tyrosine kinases such as VEGF receptors, inhibits angiogenesis and experimental choroidal neovascularization (CNV). Pazopanib inhibited VEGF expression by retinal pigment epithelium (RPE) cells and choroidal endothelial cells (CEC), decreased VEGF-induced cellular migration in a dose-dependent manner and suppressed extracellular signal-regulated kinase (ERK)-1/-2 phosphorylation. To assess the impact of pazopanib in vivo, CNV was induced in rats by rupturing the Bruch's membrane by laser coagulation. These experiments demonstrated that twice-daily topical eye drop treatment significantly (P<0.001) decreased leakage from photocoagulated lesions by 89.5%. Furthermore, the thickness of the developed CNV lesions was significantly inhibited by 71.7% (P<0.001) in pazopanib-treated eyes, and immunoreactivity of VEGF was lower than in control eyes. Our data suggest that pazopanib is a promising inhibitor of angiogenesis leading to an effective inhibition of CNV development in vivo. This activity can be largely ascribed to the down-regulation of VEGF release in the retina as well as to impaired VEGF-induced signaling and chemotaxis. Using a convenient topical dosing regimen, pazopanib may prove useful for treating a variety of ocular neovascular diseases such as neovascular age-related macular degeneration.
authors.affiliation: Department of Ophthalmology and Eye Hospital, University of Leipzig, D-04103 Leipzig, Germany.
authors.forename: Yousef
authors.initials: Y
authors.lastname: Yafai
authors.forename: Xiu Mei
authors.initials: XM
authors.lastname: Yang
authors.forename: Marc
authors.initials: M
authors.lastname: Niemeyer
authors.forename: Akiko
authors.initials: A
authors.lastname: Nishiwaki
authors.forename: Johannes
authors.initials: J
authors.lastname: Lange
authors.forename: Peter
authors.initials: P
authors.lastname: Wiedemann
authors.forename: Andrew G
authors.initials: AG
authors.lastname: King
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Yasukawa
authors.forename: Wolfram
authors.initials: W
authors.lastname: Eichler
mesh_terms: D000287:Administration, Topical; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D002829:Choroid / Q000098:blood supply* / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects / Q000473:pathology; D006801:Humans; D007191:Indazoles; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D008268:Macular Degeneration / Q000150:complications / Q000188:drug therapy; D008297:Male; D009389:Neovascularization, Pathologic / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D007191:Indazoles; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013449:Sulfonamides; D042461:Vascular Endothelial Growth Factor A; C516667:pazopanib; D020794:Receptor Protein-Tyrosine Kinases