PTK787/ZK222584, an inhibitor of vascular endothelial growth factor receptor tyrosine kinases, decreases glioma growth and vascularization.
OBJECTIVE
The aim of this study was to test the efficacy of PTK787/ZK222584, an inhibitor of vascular endothelial growth factor (VEGF) receptor tyrosine kinases, on VEGF-dependent glioma vascularization and growth.


METHODS
C6 rat glioma cells were transfected with VEGF(164) in a sense (V(+)) or antisense (V(-)) direction. Spheroids generated from V(+) or V(-) cells were implanted orthotopically into 60 rat brains. Expression of VEGF and fetal liver kinase-1 (VEGF receptor 2) was assessed immunohistochemically. Animals with V(+) gliomas received orally administered PTK787/ZK222584 on postoperative Day (POD) 1 to 12 or POD 7 to 12. Untreated animals served as negative controls, and animals with V(-) gliomas served as positive controls. Growth and vascularization were evaluated by magnetic resonance imaging and immunohistochemistry.


RESULTS
Flk-1 expression was positive within tumor vessels in V(+) gliomas, whereas all C6 clones were negative for fetal liver kinase-1 in vitro. Early (POD 1-12) and delayed (POD 7-12) application of PTK787/ZK222584 in V(+) glioma-bearing animals resulted in a significant reduction of tumor size (71% and 36%, P < 0.05) as measured by magnetic resonance imaging volumetry. Early treated V(+) gliomas reached similar volumes compared with V(-) gliomas. Vessel density was significantly reduced (42.3% and 25.7%, P < 0.05), and areas of intratumoral necrosis were enlarged (by 1.7-fold after early treatment). Additionally, proliferation was decreased by 89% and 72% (P < 0.05). There was no growth-inhibiting effect of PTK787/ZK222584 on V(-) cells observed.


CONCLUSIONS
PTK787/ZK222584 significantly halted VEGF-mediated glioma growth by inhibition of neovascularization and proliferation, providing a promising new tool in malignant glioma therapy.
Goldbrunner
Roland H
RH
Department of Neurosurgery, University of Munich, Munich, Germany. roland.goldbrunner@med.uni-muenchen.de
Bendszus
Martin
M
Wood
Jeanette
J
Kiderlen
Michael
M
Sasaki
Masato
M
Tonn
Jörg-Christian
JC
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000473:pathology; D001932:Brain Neoplasms / Q000098:blood supply* / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects*; D005910:Glioma / Q000098:blood supply* / Q000473:pathology*; D008297:Male; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000473:pathology*; D010793:Phthalazines / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors*; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects* / Q000637:transplantation*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
D020533:Angiogenesis Inhibitors; D010793:Phthalazines; D011725:Pyridines; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; C404768:vatalanib; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor