Simultaneous but not prior inhibition of VEGF165 enhances the efficacy of photodynamic therapy in multiple models of ocular neovascularization.
OBJECTIVE
To investigate the effect of the combined treatment of photodynamic therapy and specific VEGF165 inhibition with pegaptanib sodium (Macugen; Eyetech Pharmaceuticals, Lexington, MA) on ocular neovascularization.


METHODS
Photodynamic therapy's (PDT's) effects on the integrity of pegaptanib sodium were analyzed by HPLC, a VEGF165-binding assay, and a VEGF165-induced tissue factor gene expression assay. The effects of mono- or combined treatment on vessel growth and regression were determined in a murine corneal neovascularization model. The effects of combined treatment on vessel growth were also determined in a murine choroidal neovascularization model.


RESULTS
PDT did not affect the chemical composition of pegaptanib sodium nor the efficacy of pegaptanib sodium in the inhibition of VEGF165 binding to Flt-1 and VEGF165-induced gene expression. In an animal model of effects on existing ocular neovascular lesions (corneal neovascularization), PDT monotherapy yielded an initial regression of these vessels, but there followed a rapid regrowth. In contrast, pegaptanib sodium monotherapy yielded little regression but potently abrogated further vessel growth. The combination of pegaptanib sodium and PDT resulted in the regression of the neovascular lesions, as observed with PDT alone, but also prevented significant vessel regrowth, leading to a significantly greater reduction in lesion size than did each monotherapy. In addition, there was a significantly greater effect of the combination of pegaptanib sodium and PDT on lesion size in choroidal neovascularization than with each monotherapy. Pretreatment with pegaptanib sodium appeared to decrease the efficacy of PDT-induced vessel regression in corneal neovascularization, and as such the enhanced efficacy over monotherapy when the agents were delivered simultaneously was not observed.


CONCLUSIONS
Although the combined simultaneous treatment of ocular neovascularization with PDT and pegaptanib sodium may provide a more effective approach for the regression and overall treatment of CNV associated with AMD, the order of addition of these treatments may play a role in achieving optimal efficacy.
Ju
Meihua
M
(OSI) Eyetech Pharmaceuticals, Farmingdale, NY, USA.
Mailhos
Carolina
C
Bradley
John
J
Dowie
Tracy
T
Ganley
Mary
M
Cook
Gary
G
Calias
Perry
P
Lange
Norbert
N
Adamis
Anthony P
AP
Shima
David T
DT
Robinson
Gregory S
GS
D000818:Animals; D052157:Aptamers, Nucleotide / Q000627:therapeutic use*; D020256:Choroidal Neovascularization / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002851:Chromatography, High Pressure Liquid; D003315:Cornea / Q000098:blood supply; D016510:Corneal Neovascularization / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000627:therapeutic use; D011166:Porphyrins / Q000627:therapeutic use; D012333:RNA, Messenger / Q000378:metabolism; D013925:Thromboplastin / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism; D000077362:Verteporfin
D052157:Aptamers, Nucleotide; D017319:Photosensitizing Agents; D011166:Porphyrins; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D000077362:Verteporfin; C495058:pegaptanib; D013925:Thromboplastin; C501163:Flt1 protein, mouse; D040281:Vascular Endothelial Growth Factor Receptor-1