Combined inhibition of vascular endothelial growth factor and platelet-derived growth factor signaling: effects on the angiogenesis, microcirculation, and growth of orthotopic malignant gliomas.
OBJECTIVE
The goal of this study was to determine the effects of SU6668, a polyvalent receptor tyrosine kinase inhibitor against vascular endothelial growth factor receptor-2, platelet-derived growth factor receptor-beta, and fibroblast growth factor-1 on tumor growth, angiogenesis, and microcirculation in an orthotopic malignant glioma model.


METHODS
Fluorescently labeled C6 malignant glioma cells were implanted into a long-term cranial window, which had been prepared in nude mice. The animals were treated with intraperitoneal injections of SU6668 (75 mg/kg/day) immediately (five animals) or 7 days (five animals) following tumor implantation. Control mice received intraperitoneal injections of vehicle (50 microl dimethylsulfoxide) immediately (five animals) or 7 days (four animals) after tumor implantation. Tumor growth, angiogenesis, and microcirculation were assessed by performing intravital fluorescence videomicroscopy over a 14-day observation period. To assess the effects of SU6668 on overall survival, C6 glioma cells were implanted stereotactically into the brains of 24 additional animals and treatment was initiated on Day 7. In both the immediate and delayed experimental setting, SU6668 treatment resulted in a significant reduction of total and functional tumor vessel densities (both p < 0.05), reflecting a suppression of angiogenesis and impairment of tumor perfusion. As a consequence, tumor growth was significantly inhibited (p < 0.05). Histological analysis demonstrated reduced tumor growth and less mass effect on the adjacent brain of treated animals. The survival experiments confirmed the importance of our results in that survival was significantly prolonged following SU6668 therapy (p < 0.05).


CONCLUSIONS
Targeting of multiple angiogenic signaling pathways by polyvalent tyrosine kinase inhibitors represents a promising strategy to interfere with the vascularization, microcirculation, and growth of angiogenesis-dependent tumors. This also applies to malignant gliomas, despite the uniqueness of the cerebral microenvironment and the singular pathobiology of this tumor entity.
Farhadi
Mohammad Reza
MR
Department of Neurosurgery, University Hospital, Faculty of Clinical Medicine, University of Heidelberg, Mannheim, Germany.
Capelle
Hans Holger
HH
Erber
Ralf
R
Ullrich
Axel
A
Vajkoczy
Peter
P
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000473:pathology; D001932:Brain Neoplasms / Q000098:blood supply*; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000473:pathology; D005910:Glioma / Q000098:blood supply*; D007211:Indoles / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D008833:Microcirculation / Q000187:drug effects / Q000502:physiology; D008856:Microscopy, Fluorescence; D018715:Microscopy, Video; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000473:pathology / Q000503:physiopathology*; D000078183:Oxindoles; D010982:Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors* / Q000502:physiology; D011422:Propionates; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011758:Pyrroles / Q000494:pharmacology*; D051381:Rats; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000037:antagonists & inhibitors / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D014183:Transplantation, Heterologous; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000502:physiology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000502:physiology
D007211:Indoles; D000078183:Oxindoles; D010982:Platelet-Derived Growth Factor; D011422:Propionates; D011758:Pyrroles; D042461:Vascular Endothelial Growth Factor A; C412603:orantinib; D011505:Protein-Tyrosine Kinases; D020797:Receptor, Platelet-Derived Growth Factor beta; D040301:Vascular Endothelial Growth Factor Receptor-2