Antiangiogenic effects of tivozanib, an oral VEGF receptor tyrosine kinase inhibitor, on experimental choroidal neovascularization in mice.

Abstract

We investigated the effects of tivozanib, an oral vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor, on experimental choroidal neovascularization (CNV) in mice. C57BL/6 mice were treated with tivozanib (1 mg/kg/day) or vehicle at the onset (day 0) of the study and experimental CNV was induced by laser photocoagulation the following day. In the other groups, tivozanib or vehicle was started 7 days after the laser photocoagulation to determine the effects of the drug on established CNV. To evaluate changes in the CNV lesions, choroidal flat mounts, fluorescein angiography, immunofluorescence staining with isolectin B4, and histological examinations were performed 14 days after CNV induction. Expression of phosphorylated ERK1/2 in choroidal tissues was measured by western blot analysis to demonstrate the inhibitory effect of tivozanib on intracellular signaling pathways involved in CNV development. Compared to vehicle-treatment, tivozanib suppressed the development of CNV lesions and led to a significant regression of established CNV, reducing the affected areas by 80.7% and 67.7%, respectively. On fluorescein angiography, tivozanib-treated mice had significantly less fluorescence leakage than vehicle-treated mice (P < 0.001). On immunofluorescence staining, the isolectin B4-labeled area was smaller in tivozanib-treated mice (P < 0.001). Phosphorylated ERK 1/2 levels increased after CNV induction by laser application and were suppressed by tivozanib treatment. Tivozanib effectively inhibited the progression of CNV in an experimental CNV model. These results suggest that tivozanib may be a therapeutic alternative for the treatment of neovascular age-related macular degeneration.