Combretastatin A-4 phosphate suppresses development and induces regression of choroidal neovascularization.
OBJECTIVE
Combretastatin A-4 (CA-4) is a naturally occurring agent that binds tubulin and causes necrosis and shrinkage of tumors by damaging their blood vessels. In this study the effect of a CA-4 prodrug, combretastatin A-4-phosphate (CA-4-P), was tested in two models of ocular neovascularization.


METHODS
The effect of CA-4-P was quantitatively assessed in transgenic mice with overexpression of vascular endothelial growth factor in the retina (rho/VEGF mice) and mice with choroidal neovascularization (CNV) due to laser-induced rupture of Bruch's membrane.


RESULTS
In rho/VEGF mice, daily intraperitoneal injections of 4.0 mg/kg CA-4-P starting at postnatal day (P)7, the time of onset of transgene expression, resulted in a significant reduction in the number of neovascular lesions and total area of neovascularization per retina at P21, compared with vehicle-injected mice. In mice with laser-induced rupture of Bruch's membrane, daily intraperitoneal injections of 75 or 100 mg/kg CA-4-P resulted in a significant reduction in the area of CNV at rupture sites compared with vehicle-injected mice. In mice with established CNV, daily intraperitoneal injections of 100 mg/kg CA-4-P for 1 week resulted in a significant reduction in CNV area at rupture sites compared with the baseline area before treatment or the area of CNV in vehicle-treated mice.


CONCLUSIONS
These data indicate that CA-4-P suppresses the development of VEGF-induced neovascularization in the retina and both blocks development and promotes regression of CNV. Therefore, CA-4-P shows potential for both prevention and treatment of ocular neovascularization.
Nambu
Hiroyuki
H
Department of Ophthalmology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Nambu
Rie
R
Melia
Michele
M
Campochiaro
Peter A
PA
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D020256:Choroidal Neovascularization / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology / Q000517:prevention & control; D004195:Disease Models, Animal; D016228:Endothelial Growth Factors; D005260:Female; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011355:Prodrugs / Q000627:therapeutic use*; D012074:Remission Induction; D012243:Rhodopsin / Q000378:metabolism; D013267:Stilbenes / Q000627:therapeutic use*; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D000972:Antineoplastic Agents, Phytogenic; D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D011355:Prodrugs; D013267:Stilbenes; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D012243:Rhodopsin; C058728:fosbretabulin