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The Synergistic Action of a VEGF‐Receptor Tyrosine‐Kinase Inhibitor and a Sensitizing PDGF‐Receptor Blocker Depends upon the Stage of Vascular Maturation
Author(s) -
Hlushchuk Ruslan,
Baum Oliver,
Gruber Guenther,
Wood Jeanette,
Djonov Valentin
Publication year - 2007
Publication title -
microcirculation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.793
H-Index - 83
eISSN - 1549-8719
pISSN - 1073-9688
DOI - 10.1080/10739680701370021
Subject(s) - platelet derived growth factor receptor , chorioallantoic membrane , vascular endothelial growth factor , receptor , tyrosine kinase inhibitor , receptor tyrosine kinase , angiogenesis , tyrosine kinase , growth factor , platelet derived growth factor , endocrinology , biology , medicine , pericyte , tunel assay , kinase insert domain receptor , cancer research , vascular endothelial growth factor a , endothelial stem cell , vegf receptors , immunohistochemistry , cancer , biochemistry , in vitro
Objective: To investigate the effects of tyrosine‐kinase inhibitors of vascular endothelial growth factor (VEGF) and platelet‐derived growth factor (PDGF)‐receptors on non‐malignant tissue and whether they depend upon the stage of vascular maturation. Materials and methods: PTK787/ZK222584 and CGP53716 (VEGF‐ and PDGF‐receptor inhibitor respectively), both alone and combined, were applied on chicken chorioallantoic membrane (CAM). Results: On embryonic day of CAM development (E)8, only immature microvessels, which lack coverage of pericytes, are present; whereas the microvessels on E12 have pericytic coverage. This development was reflected in the expression levels of pericytic markers (α ‐smooth muscle actin, PDGF‐receptor ß and desmin), which were found by immunoblotting to progressively increase between E8 and E12. Monotherapy with 2 μ g of PTK787/ZK222584 induced significant vasodegeneration on E8, but not on E12. Monotherapy with CGP53716 affected only pericytes. When CGP53716 was applied prior to treatment with 2 μ g of PTK787/ZK222584, vasodegeneration occurred also on E12. The combined treatment increased the apoptotic rate, as evidenced by the cDNA levels of caspase‐9 and the TUNEL‐assay. Conclusion: Anti‐angiogenic treatment strategies for non‐neoplastic disorders should aim to interfere with the maturation stage of the target vessels: monotherapy with VEGF‐receptor inhibitor for immature vessels, and combined anti‐angiogenic treatment for well developed mature vasculature.