Abstract
Currently available compounds that interfere with VEGF-A signalling effectively inhibit angiogenesis in gliomas, but influence diffuse infiltrative growth to a much lesser extent. Development of a functional tumour vascular bed not only involves VEGF-A but also requires platelet-derived growth factor receptor-β (PDGFRβ), which induces maturation of tumour blood vessels. Therefore, we tested whether combined inhibition of VEGFR and PDGFRβ increases therapeutic benefit in the orthotopic glioma xenograft models E98 and E473, both displaying the diffuse infiltrative growth that is characteristically observed in most human gliomas. We used bevacizumab and vandetanib as VEGF(R) inhibitors, and sunitinib to additionally target PDGFRβ. We show that combination therapy of sunitinib and vandetanib does not improve therapeutic efficacy compared to treatment with sunitinib, vandetanib or bevacizumab alone. Furthermore, all compounds induced reduction of vessel leakage in compact E98 tumour areas, resulting in decreased detectability of these mostly infiltrative xenografts in Gd-DTPA-enhanced MRI scans. These data show that inhibition of VEGF signalling cannot be optimized by additional PDGFR inhibition and support the concept that diffuse infiltrative areas in gliomas are resistant to anti-angiogenic therapy.
Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Angiogenesis Inhibitors / pharmacology
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Angiogenesis Inhibitors / therapeutic use*
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Animals
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Antibodies, Monoclonal / pharmacology
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Antibodies, Monoclonal / therapeutic use
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Antibodies, Monoclonal, Humanized
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Antineoplastic Agents / pharmacology
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Antineoplastic Agents / therapeutic use*
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Antineoplastic Combined Chemotherapy Protocols / pharmacology
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Antineoplastic Combined Chemotherapy Protocols / therapeutic use
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Bevacizumab
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Blood-Brain Barrier / drug effects
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Brain Neoplasms / blood supply
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Brain Neoplasms / drug therapy*
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Glioma / blood supply
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Glioma / drug therapy*
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Humans
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Indoles / administration & dosage
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Indoles / pharmacology
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Indoles / therapeutic use
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Magnetic Resonance Imaging / methods
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Mice
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Mice, Nude
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Neovascularization, Pathologic / drug therapy
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Piperidines / administration & dosage
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Piperidines / pharmacology
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Piperidines / therapeutic use
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Pyrroles / administration & dosage
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Pyrroles / pharmacology
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Pyrroles / therapeutic use
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Quinazolines / administration & dosage
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Quinazolines / pharmacology
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Quinazolines / therapeutic use
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Receptor, Platelet-Derived Growth Factor beta / antagonists & inhibitors
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Signal Transduction / drug effects
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Sunitinib
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Vascular Endothelial Growth Factor A / antagonists & inhibitors
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Xenograft Model Antitumor Assays
Substances
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Angiogenesis Inhibitors
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Antibodies, Monoclonal
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Antibodies, Monoclonal, Humanized
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Antineoplastic Agents
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Indoles
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Piperidines
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Pyrroles
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Quinazolines
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Vascular Endothelial Growth Factor A
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Bevacizumab
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Receptor, Platelet-Derived Growth Factor beta
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Sunitinib
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vandetanib