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.
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 ratglioma 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.
Authors: Meser M Ali; Branislava Janic; Abbas Babajani-Feremi; Nadimpalli R S Varma; A S M Iskander; John Anagli; Ali S Arbab Journal: PLoS One Date: 2010-01-15 Impact factor: 3.240