Inhibition of choroidal neovascularization in mice by systemic administration of the multikinase inhibitor, sorafenib

Abstract

[영문]

Choroidal neovascularization (CNV) is known to be the leading cause of irreversible vision loss in patients with age-related macular degeneration. A variety of preclinical and clinical studies suggest that vascular endothelial growth factor (VEGF) is a central player in pathologic neovascularization in the eye. Although VEGF clearly has a central role in the development of neovascular diseases, other growth factor pathways, including those that signal through additional receptor tyrosine kinases, such as platelet-derived growth factor receptor (PDGFR) and fibroblast growth factor receptors (FGFRs), have also been implicated in neovascularization and ocular diseases. Sorafenib (Nexavar®, Bay-43-9006, Bayer Schering Pharma, Germany) is a novel multikinase inhibitor that was recently approved by the Food and Drug Administration for the treatment of renal cell carcinoma. In addition to Raf kinases, several other kinases, including VEGFR2, VEGFR3 and PDGFR-β, are inhibited by sorafenib.This study is to explore the anti-angiogenic properties of sorafenib in an animal model of CNV. Sorafenib or vehicle was administered orally to female C57BL/6 mice at the onset (day 0) of experiments. CNV was induced by laser photocoagulation the following day. After 14 days, mice were perfused with fluorescein-labeled dextran, and the area of CNV was measured on choroidal flat mounts by image analysis. In some groups of mice, treatments were started 7 days after the laser photocoagulation to determine the effect of the agent on established CNV. Expression of phosphorylated extracellular signal-regulated kinase (p-ERK) in choroidal tissues was measured by Western-blot analysis to demonstrate the kinase inhibitory effect of sorafenib in intracellular signaling pathways involved in CNV formation. Sorafenib significantly reduced the extent of CNV in a dose-dependent manner. The area of CNV was reduced by 43% in the 30­mg?kg 1?day 1 group and by 61% in the 60-mg?kg 1?day 1 group compared with vehicle-treated controls (both P < 0.0001). Oral administration of sorafenib also caused significant regression of established CNV. The area of CNV was reduced by 59% in the 30-mg?kg 1?day 1 group and by 66% in the 60­mg?kg 1?day 1 group compared with both baseline and control measurements (P < 0.0001). The expression of p-ERK in choroidal tissues was increased within 1 day of laser photocoagulation and remained elevated for 2 weeks. The expression of p-ERK was suppressed by sorafenib.In conclusion, the current study showed that oral administration of the multikinase inhibitor sorafenib significantly suppressed the development of laser-induced CNV and caused regression of established CNV in mice. Sorafenib interferes with multiple pro-angiogenic receptor tyrosine kinases, including VEGFR 2, PDGFR-β and Raf kinase, and thus holds promise for the treatment of CNV in clinical settings.