Journal article

Angiostatic kinase inhibitors to sustain photodynamic angio-occlusion

Targeted angiostatic therapy receives major attention for the treatment of cancer and exudative age-related macular degeneration (AMD). Photodynamic therapy (PDT) has been used as an effective clinical approach for these diseases. Since PDT can cause an angiogenic response in the treated tissue, combination of PDT with anti-angiogenic compounds should lead to improved therapy. The current study was undertaken to test the clinically used small molecule kinase inhibitors Nexavar(®) (sorafenib), Tarceva(®) (erlotinib), and Sutent(®) (sunitinib) for this purpose, and compare the results to the combination of Visudyne(®)-PDT with Avastin(®) (bevacizumab) treatment. When topically applied to the chicken chorioallantoic membrane (CAM) at embryo development day (EDD) 7, a clear inhibition of blood vessel development was observed, with sorafenib being most efficient. To investigate combination with phototherapy, Visudyne(®)-PDT was first applied on EDD11 to close all <100 μm vessels. Application of angiostatics after PDT resulted in a significant decrease in vessel regrowth in terms of reduced vessel density and number of branching points/mm(2). While for all compounds the 50% effective dose (ED(50)) was approximately 10-fold lower, sorafenib also outperformed the other compounds. In vitro, all kinase inhibitors decreased the viability of human umbilical vein endothelial cells (HUVEC). Sunitinib convincingly inhibited the in vitro migration of endothelial cells. These results suggest the therapeutic potential of these compounds for application in combination with PDT in anti-cancer approaches, and possibly also in the treatment of other diseases where angiogenesis plays an important role.


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