Evaluation of the vascular targeting agent combretastatin a-4 prodrug on retinal neovascularization in the galactose-fed dog.
OBJECTIVE
Combretastatin A-4 (CA-4) is a vascular targeting agent known to rapidly shut off blood flow in new vessels and, as a result, regress neovascularization. In this pilot study, the ability of CA-4 to modify retinal neovascularization, which results in altered retinal vessel blood flow and retinal permeability, was evaluated in aphakic long-term galactose-fed beagles, an animal model that develops diabetes-like retinal neovascularization.


METHODS
Two (2) groups of aphakic dogs, each group comprised of 4 galactose-fed dogs and 2 age-matched controls dogs, were utilized. Each group initially received the combretastatin A-4-phosphate prodrug (CA-4P) as either sub-Tenon's injections, administered at the corneoscleral junction, or intravitreal injections. Six (6) weeks after this treatment, all dogs also received systemic (intravenous) injections of CA-4P. Retinal vascular changes were monitored at 2-week intervals by fluorescein angiography.


RESULTS
All galactose-fed dogs demonstrated the presence of retinal neovascular lesions by fluorescein angiograms. Fluorescein leakage or perfusion through neovascular vessels was not altered by either sub-Tenon's, intravitreal, or systemic CA-4P administration. Whereas CA-4P was well tolerated by the healthy eyes of the control animals, its administration to some galactose-fed dogs was associated with corneal edema and increases in intraocular pressure following sub-Tenon's and intraocular injections.


CONCLUSIONS
Neovascularization in the galactose-fed dog progresses over a period of years, similar to that observed with clinical diabetic retinopathy. The failure of CA-4P to ameliorate neovascularization suggests that chronic, long-term administration may be required to destroy the slowly growing retinal endothelial cells.
Kador
Peter F
PF
Laboratory of Ocular Therapeutics, National Eye Institute, National Institutes of Health, Bethesda, MD, USA. pkador@unmc.edu
Blessing
Karen
K
Randazzo
James
J
Makita
Jun
J
Wyman
Milton
M
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000494:pharmacology*; D001035:Aphakia; D003930:Diabetic Retinopathy / Q000139:chemically induced / Q000188:drug therapy*; D004195:Disease Models, Animal; D004285:Dogs; D005451:Fluorescein Angiography; D005690:Galactose; D007267:Injections; D007429:Intraocular Pressure / Q000187:drug effects; D011355:Prodrugs / Q000008:administration & dosage / Q000494:pharmacology*; D015861:Retinal Neovascularization / Q000139:chemically induced / Q000188:drug therapy*; D012171:Retinal Vessels / Q000187:drug effects / Q000473:pathology; D013267:Stilbenes / Q000008:administration & dosage / Q000494:pharmacology*
D000972:Antineoplastic Agents, Phytogenic; D011355:Prodrugs; D013267:Stilbenes; C058728:fosbretabulin; D005690:Galactose