Angiostatin Inhibits and Regresses Corneal Neovascularization

Abstract

To determine the ability of angiostatin and the angiostatin-producing low-metastatic (LM) clone of Lewis lung carcinoma (LLC) to inhibit and regress corneal neovascularization, as compared with the nonangiostatin-producing high-metastatic (HM) clone. Methods: Three groups of C57BL6/J mice underwent chemical and mechanical denudation of corneal and limbal epithelium. One group remained tumor free while the other 2 were implanted with LLC cells (either the HM or LM clones) subcutaneously the day before, 2 weeks after, or 4 weeks after denudation. Corneas were harvested 2 weeks after tumor implantation (at 2, 4, and 6 weeks after denudation for tumor-free mice). Neovascularization was quantified by CD31 immunostaining. In a second experiment, recombinant angiostatin was delivered continuously for 2 weeks via an osmotic pump in mice with established corneal neovascularization. Results: The mean percentages of neovascularized corneal area in mice 2 weeks after LM-LLC implantation were 4.6%, 3.7%, and 37.0%, at 2, 4, and 6 weeks after scraping, respectively. In contrast, in the mice implanted with HM-LLC, the corresponding values were 45.4% (P=.01), 90.1% (P=.03), and 80.3% (P=.005). For tumor-free mice, the corresponding values were 62.0% (P=.003), 68.9% (P=.03), and 59.3% (P=.06). Mice implanted with angiostatin pumps had a 37.7% neovascularized corneal area 2 weeks after implantation and 4 weeks after scraping while mice implanted with sham pumps had 60.5% (P=.007). Conclusion: Angiostatin inhibits and regresses corneal neovascularization induced by mechanical and alkali corneal injury.

Subconjunctival gene delivery of the transcription factor GA-binding protein delays corneal neovascularization in a mouse model

“…7 Recent studies have shown that angiogenesis inhibitors, such as endostatin, angiostatin, somatostatin, tissue inhibitor of metalloproteinase-3, peptide derived from thrombospondin-1, prolactin and brain-specific angiogenesis inhibitor 1 (BAI1), can inhibit corneal neovascularization and maintain corneal avascularity. [9][10][11][12][13][14][15][16] GA-binding protein (GABP) is a ubiquitously expressed nuclear transcription factor that is involved in a broad range of cellular processes and that regulates target gene expression in the cell cycle and cellular metabolism. 17 GABP is composed of two subunits: GABPa contains the erythroblast transformation-specific DNA-binding domain, whereas the substitutable subunit, GABPb or GABPg, contains ankyrin repeats and the transcriptional activation domain.…”

Effects of endostatin-vascular endothelial growth inhibitor chimeric recombinant adenoviruses on antiangiogenesis

“…Researches indicated that angiogenesis inhibitors were highly potent in suppressing angiogenesis which could enable the tumor mass to remain in a dormant state [1][2][3][4] and inhibit the development of corneal neovascularization [5][6][7] . Endostatin could cause G(1) cell cycle arrest in endothelial cells, inhibit endothelial cell proliferation and migration, and promote apoptosis [8] .…”

Lipid-mediated delivery of brain-specific angiogenesis inhibitor 1 gene reduces corneal neovascularization in an in vivo rabbit model

“…These include medication, laser photocoagulation, and surgery. Several angiogenesis inhibitors have been identified and tried as medical treatment, including prolactin, 3 endostatin, 7 angiostatin, 8 somatostatin, 9 cyclosporin A, 18 TNP-470, 19 steroids, 20 nonsteroidal antiinflammatory drugs, 21 thalidomide, 22 methotrexate, 23 and culture supernatant of human amniotic cells. 24 Recently, targeted macrophage metalloelastase or angiostatin gene transfer has been tried to halt angiogenesis in a mouse tumor model, 25,26 and naked plasmids have been shown to be taken up by corneal epithelium.…”

“…[3][4][5] Recognition of the potential benefits of controlling angiogenesis has led to a search for angiogenesis inhibitors. 6 Several angiogenesis inhibitors have been identified, such as prolactin, 3 endostatin, 7 angiostatin, 8 somatostatin, 9 and peptide derived from thrombospondin-1 (TSP1), 10 although some of which are the fragments of larger proteins. However, there have been a few studies of gene delivery as a way to reduce neovascularization in the eye.…”