TY - JOUR
T1 - Combretastatin A-4 phosphate suppresses development and induces regression of choroidal neovascularization
AU - Nambu, Hiroyuki
AU - Nambu, Rie
AU - Melia, Michele
AU - Campochiaro, Peter A.
PY - 2003/8/1
Y1 - 2003/8/1
N2 - PURPOSE. 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.
AB - PURPOSE. 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.
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U2 - 10.1167/iovs.02-0985
DO - 10.1167/iovs.02-0985
M3 - Article
C2 - 12882819
AN - SCOPUS:0042343848
SN - 0146-0404
VL - 44
SP - 3650
EP - 3655
JO - Investigative Ophthalmology and Visual Science
JF - Investigative Ophthalmology and Visual Science
IS - 8
ER -