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DISCUSSION
Many drugs have been identified as inhibitors in experimental and clinical corneal neovascularization, including steroids, rapamycin, nonsteroidal antiinflammatory drugs, ciclosporin A, thalidomide and so on. Among these drugs, steroids seem to be the best therapy, which can inhibit corneal neovascularization by inhibiting inflammation [2]. Apart from the immunosuppressive effects, steroids, it also changes the cell membrane structure and destructed the basement membrane and plays a role in antiangiogenesis. However, the maturity of the vessels and the approach of angiogenesis impact the results of treatment [3]. The corneal neovascularization model experiment has proved that VEGF played an important role in the process of angiogenesis[4]. So inhibiting VEGF can be effective in the treatment of corneal neovascularization in ocular surface diseases.
Figure 1 At the 14th day following corneal alkali burns CNV in control group (group1) and subconjunctivalinjection group of Bevacizumab (group 4)（略）
Figure 2 At the 16th day following corneal alkali burns histopathological examination for CNV in control group(group1) and subconjunctivalinjection group of Bevacizumab (group 4)（HE×400）（略）
Figure 3 Positive staining for VEGF in control group (group 1) is stronger than the subconjunctivalinjection group of Bevacizumab (group 4）（HE ×400）（略）
Bevacizumab (Avastin; Genentech Inc), is an FDAapproved recombinant, humanized monoclonal antibody against VEGFA drug ,that is used for treating advanced colorectal cancer[5]. Recently, Application of bevacizumab has promising results. Bevacizumab has been successfully absorbed systemically and intravitreally in humans with exudative age related macular degeneration, diabetic retinopathy, choroids and iris neovascularization, but with minimal or no adverse effects [6]. There are experiments show that bevacizumab in the 5mg/mL or below this level, compared with control group, there is no significant difference in cell activity and no significant cytotoxicity in human corneal cells in vitro [7].
The results of our research show that bevacizumab inhibit CNV effectively in all the rats of treatment group, and the data show out the statistical significance, which is in line with the literature [8]. But the inhibition of corneal neovascularization was far from perfect, a possible explain is that diffusion and absorption of bevacizumab through the conjunctiva reduce partial inhibition activity of VEGF. At the same time, it should be recognized that the formation of corneal neovascularization involves many factors, e.g. transforming growth factor α and β, and fibroblast growth factor.
Comprehensive treatment should be considered within the framework.
Subconjunctival injection, a conventional option for drug delivery method, is convent and simple to be performed, and has minimal related complications. In all the rats of our experiment, bevacizumab injectionrelated side effects were not observed. This experiment shows that bevacizumab can inhibit corneal angiogenesis in all tested groups. At present there are a few clinical reports[9,10]:Topical eyedrop of bevacizumab(5mg/L) , five patients with corneal neovascularization were under control, some of them had CNV regression; two cases of corneal transplants and limbal stem cells diseases treated with subconjunctival Bevacizumab of 2.5 mg had regression of newly formed vessels. These findings proved that Bevacizumab is effective in controlling corneal neovascizularizetion in a shortterm period. Clinical data and retrospective analysis on the effects of Bevacizumab should be done to investigate how long the inhibition of CNV can persist. We have shown that bevacizumab is efficacious in limiting corneal neovascularization in an animal model. The next step is to use bevacizumab in controlled clinical trial for the treatment of corneal neovascularization or for highrisk corneal graft recipients.
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