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Chiho Shoda, Yukihiro Miwa, Ayako Ishida, Satoru Yamagami, Kazuo Tsubota, Toshihide Kurihara; HIF inhibitor topotecan suppresses choroidal neovascularization and fibroproliferation in mice. Invest. Ophthalmol. Vis. Sci. 2019;60(9):1254.
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© ARVO (1962-2015); The Authors (2016-present)
Age-related macular degeneration is a major vision threatening disorder in developed countries. At present, anti-VEGF therapy and photodynamic therapy are shown to be effective against exudative age-related macular degeneration while it is difficult to prevent chorioretinal atrophy and fibrotic scar only with these treatments. Hypoxia-inducible factors (HIFs) are transcriptional factors which regulate angiogenesis and other hypoxia responces mainly depending on oxygen availability and can be a new therapeutic target in addition to VEGF. We hypothesized that ectopic activation of HIFs may contribute to the pathogenesis of the diseases through an abnormal stress response. In this study, we investigated therapeutic effect of a topoisomerase inhibitor topotecan, which suppresses HIF synthesis, against pathological angiogenesis and fibroproliferation in a murine model of laser-induced choroidal neovascularization (CNV).
To evaluate therapeutic effect of topotecan on CNV and fibrosis, 5 laser spots(532 nm, 200 mW, 100 milliseconds, 75 μm) were applied to each eye in 7-week-old male C57BL/6J mice to induce choroidal neovascularization and fibroproliferation. After laser irradiation, mice were injected vehicle or topotecan (2.5 mg/kg/day for 5 consecutive days for CNV, 0.625 mg/kg/day for 5 weeks, 5 times a week, for fibroproliferation) intraperitoneally. CNV and choroidal fibrous tissue was measured on choroidal wholemount staining with isolectin B4 or type 1 collagen1a on days 7 or 35 and was observed using a confocal fluorescence microscope. The volume of CNV and fibrotic proliferation was quantified using 3D image analysis software IMARIS. P-value less than 0.05 was considered as statistical significance with Student’s t-test.
In the murine laser CNV model, the volume of CNV on day 7 after the laser irradiation was significantly smaller in the topotecan treated group (249 ± 121 μm3, p <0.0001) than that in the control group (average 704 ± 455 μm3). Choroidal fibrous tissue on day 35 after the laser irradiation was significantly smaller in the topotecan treated group (133 ± 139 μm3, p <0.05) than that in the control group (average 270 ± 159 μm3).
Pathological angiogenesis and fibroproliferation in the choroid in a murine laser-induced CNV model was suppressed by HIF inhibitor topotecan.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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