PTK787/ZK222584, an inhibitor of vascular endothelial growth factor receptor tyrosine kinases, decreases glioma growth and vascularization

Neurosurgery. 2004 Aug;55(2):426-32; discussion 432. doi: 10.1227/01.neu.0000129551.64651.74.


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.

Conclusion: PTK787/ZK222584 significantly halted VEGF-mediated glioma growth by inhibition of neovascularization and proliferation, providing a promising new tool in malignant glioma therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inhibitors / pharmacology*
  • Animals
  • Brain / pathology
  • Brain Neoplasms / blood supply*
  • Brain Neoplasms / pathology*
  • Cell Division / drug effects*
  • Cell Survival / drug effects*
  • Glioma / blood supply*
  • Glioma / pathology*
  • Male
  • Neoplasm Transplantation
  • Neovascularization, Pathologic / pathology*
  • Phthalazines / pharmacology*
  • Pyridines / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Receptors, Vascular Endothelial Growth Factor / antagonists & inhibitors*
  • Transfection
  • Tumor Cells, Cultured / drug effects*
  • Tumor Cells, Cultured / transplantation*
  • Vascular Endothelial Growth Factor A / genetics


  • Angiogenesis Inhibitors
  • Phthalazines
  • Pyridines
  • Vascular Endothelial Growth Factor A
  • vascular endothelial growth factor A, rat
  • vatalanib
  • Receptor Protein-Tyrosine Kinases
  • Receptors, Vascular Endothelial Growth Factor