The synergistic action of a VEGF-receptor tyrosine-kinase inhibitor and a sensitizing PDGF-receptor blocker depends upon the stage of vascular maturation.
OBJECTIVE
To investigate the effects of tyrosine-kinase inhibitors of vascular endothelial growth factor (VECF) and platelet-derived growth factor (PDCF)-receptors on non-malignant tissue and whether they depend upon the stage of vascular maturation.


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 (alpha-smooth muscle actin, PDGF-receptor beta and desmin), which were found by immunoblotting to progressively increase between E8 and E12. Monotherapy with 2 microg 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 microg 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.


CONCLUSIONS
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.
Hlushchuk
Ruslan
R
Institute of Anatomy, University of Bern, Bern, Switzerland.
Baum
Oliver
O
Gruber
Guenther
G
Wood
Jeanette
J
Djonov
Valentin
V
D000818:Animals; D000943:Antigens, Differentiation / Q000096:biosynthesis; D017209:Apoptosis / Q000187:drug effects; D001808:Blood Vessels / Q000254:growth & development* / Q000648:ultrastructure; D002642:Chick Embryo; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D020286:Pericytes / Q000378:metabolism* / Q000648:ultrastructure; D047428:Protein Kinase Inhibitors / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors*
D000943:Antigens, Differentiation; D047428:Protein Kinase Inhibitors; D017479:Receptors, Platelet-Derived Growth Factor; D040262:Receptors, Vascular Endothelial Growth Factor