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PTK787/ZK222584, an Inhibitor of Vascular
Endothelial Growth Factor Receptor Tyrosine Kinases, Decreases Glioma Growth and
Vascularization
Goldbrunner RH, Bendszus M, Wood J, Kiderlen M, Sasaki M, Tonn JC
Department of Neurosurgery, University of Munich, Munich,
Germany.
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.
PMID: 15271251 [PubMed - in process]
Source: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15271251
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