Anti-VEGF therapy (bevacizumab) for sulfur mustard-induced corneal neovascularization associated with delayed limbal stem cell deficiency in rabbits.
OBJECTIVE
To investigate the involvement of VEGF in corneal neovascularization (CNV) following sulfur mustard (SM) exposure and to test the therapeutic effects of bevacizumab (Avastin) in respect to dose, route of administration and timing.


METHODS
Topical bevacizumab (6 or 25 mg/ml, ×2/day) was applied to rabbit eyes, before or after appearance of NV, following SM vapor exposure, and was compared with subconjunctival injection (25 mg/ml, ×2/week) and topical dexamethasone (1%, ×4/day). Treatments were given for 3 weeks. VEGF levels were monitored by immunohistochemistry and ELISA assay. Clinical evaluations included slit-lamp examination, impression cytology for diagnosis of Limbal Stem Cell Deficiency (LSCD), pachymetry, measurement of NV length and histology.


RESULTS
Corneal NV was developed, as early as 2 weeks after exposure, in 50-70% of the eyes, associated with increased levels of VEGF. Topical bevacizumab treatment with both doses, starting at 4 weeks, reduced vascularization. Subconjunctival injection and topical dexamethasone were more potent. A combined treatment of dexamethasone and bevacizumab improved the anti-angiogenic efficacy, yet, there was no effect on LSCD. Topical bevacizumab treatment starting at 1 week, when VEGF was elevated but before appearance of NV, had no effect.


CONCLUSIONS
VEGF was involved in corneal angiogenesis in SM-induced ocular injury. Bevacizumab was beneficial in reducing CNV by both, topical or subconjunctival injection, when given as a symptomatic therapy with or without dexamethasone, however with no effect on SC deficiency. Further studies on the pathological mechanism of SM-induced ocular surface disorder may direct towards improved therapy.
Department of Pharmacology, Israel Institute for Biological Research , Ness-Ziona , Israel.
Tamar
T
Kadar
Adina
A
Amir
Liat
L
Cohen
Maayan
M
Cohen
Rita
R
Sahar
Hila
H
Gutman
Vered
V
Horwitz
Shlomit
S
Dachir
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D000068258:Bevacizumab; D003315:Cornea / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016510:Corneal Neovascularization / Q000139:chemically induced* / Q000188:drug therapy* / Q000473:pathology; D003879:Dermatologic Agents / Q000494:pharmacology; D005260:Female; D016850:Limbus Corneae / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009151:Mustard Gas / Q000494:pharmacology*; D011817:Rabbits; D013234:Stem Cells / Q000473:pathology*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D003879:Dermatologic Agents; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; D009151:Mustard Gas