Simultaneous but not prior inhibition of VEGF165 enhances the efficacy of photodynamic therapy in multiple models of ocular neovascularization
Simultaneous but not prior inhibition of VEGF165 enhances the efficacy of photodynamic therapy in multiple models of ocular neovascularization
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DOI：
10.1167/iovs.07-0195
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发表时间：
2008-02-01
影响因子：
4.4
通讯作者：
Robinson, Gregory S.
中科院分区：
文献类型：
--
作者：
Ju, Meihua;Mailhos, Carolina;Robinson, Gregory S.
目的。目的：探讨光动力疗法与pegaptanib钠（Macugen; Eyetech Pharmaceuticals, Lexington， MA）特异性抑制VEGF165联合治疗对眼部新生血管的影响。采用高效液相色谱法、vegf165结合法和vegf165诱导的组织因子基因表达法分析光动力疗法（PDT）对pegaptanib钠完整性的影响。在小鼠角膜新生血管模型中测定了单一或联合治疗对血管生长和消退的影响。在小鼠脉络膜新生血管模型中，还测定了联合治疗对血管生长的影响。PDT不影响pegaptanib钠的化学成分，也不影响pegaptanib钠抑制VEGF165与Flt-1结合和VEGF165诱导的基因表达的效果。在对现有眼部新生血管病变（角膜新生血管）影响的动物模型中，PDT单药治疗产生了这些血管的最初消退，但随后迅速再生。相比之下，单药培加他尼钠治疗几乎没有消退，但有力地消除了进一步的血管生长。与单独使用PDT观察到的结果一样，pegaptanib钠和PDT联合使用导致新血管病变的消退，但也阻止了明显的血管再生，导致病变大小的缩小明显大于单独使用PDT。此外，佩加他尼钠和PDT联合治疗对脉络膜新生血管病变大小的影响明显大于单独治疗。培加他尼钠预处理似乎降低了pdt诱导的角膜新生血管消退的疗效，因此，当两种药物同时给药时，没有观察到比单药治疗更强的疗效。虽然PDT联合佩加他尼钠同时治疗眼部新生血管可能是一种更有效的方法，可以对与AMD相关的CNV进行回归和整体治疗，但这些治疗的加入顺序可能在获得最佳疗效方面发挥作用。
PURPOSE. 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.