title: Angiostatic kinase inhibitors to sustain photodynamic angio-occlusion.
abstract: 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. As PDT can cause an angiogenic response in the treated tissue, combination of PDT with anti-angiogenic compounds should lead to improved therapy. This study was undertaken to test the clinically used small molecule kinase inhibitors Nexavar® (sorafenib), Tarceva® (erlotinib) and Sutent® (sunitinib) for this purpose, and to compare the results to the combination of Visudyne®-PDT with Avastin® (bevacizumab) treatment. When topically applied to the chicken chorioallantoic membrane at embryo development day (EDD) 7, a clear inhibition of blood vessel development was observed, with sorafenib being most efficient. To investigate the 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) . As the 50% effective dose (ED50) for all compounds was approximately 10-fold lower, Sorafenib outperformed the other compounds. In vitro, all kinase inhibitors decreased the viability of human umbilical vein endothelial cells. 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.
authors: Angiogenesis Laboratory, Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands. Patrycja.Nowak-Sliwinska@epfl.ch
authors: Patrycja
authors: P
authors: Nowak-Sliwinska
authors: Andrea
authors: A
authors: Weiss
authors: Judy R
authors: JR
authors: van Beijnum
authors: Tse J
authors: TJ
authors: Wong
authors: Jean-Pierre
authors: JP
authors: Ballini
authors: Blaise
authors: B
authors: Lovisa
authors: Hubert
authors: H
authors: van den Bergh
authors: Arjan W
authors: AW
authors: Griffioen
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology; D001557:Benzenesulfonates / Q000494:pharmacology; D000068258:Bevacizumab; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002642:Chick Embryo; D049033:Chorioallantoic Membrane / Q000098:blood supply / Q000187:drug effects*; D000069347:Erlotinib Hydrochloride; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008856:Microscopy, Fluorescence / Q000379:methods; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D010778:Photochemotherapy / Q000379:methods*; D011166:Porphyrins / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D000077157:Sorafenib; D000077210:Sunitinib; D000077362:Verteporfin; D057135:Wet Macular Degeneration / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D001557:Benzenesulfonates; D007211:Indoles; D010671:Phenylurea Compounds; D011166:Porphyrins; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011758:Pyrroles; D011799:Quinazolines; D000077362:Verteporfin; D009536:Niacinamide; D000068258:Bevacizumab; D000077157:Sorafenib; D000069347:Erlotinib Hydrochloride; D000077210:Sunitinib