AZD2171, a Pan-VEGF Receptor Tyrosine Kinase Inhibitor, Normalizes Tumor Vasculature and Alleviates Edema in Glioblastoma Patients

Using MRI techniques, we show here that normalization of tumor vessels in recurrent glioblastoma patients by daily administration of AZD2171—an oral tyrosine kinase inhibitor of VEGF receptors—has rapid onset, is prolonged but reversible, and has the significant clinical benefit of alleviating edema...

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Bibliographic Details
Published in:Cancer cell 2007, Vol.11 (1), p.83-95
Main Authors: Batchelor, Tracy T., Sorensen, A. Gregory, di Tomaso, Emmanuelle, Zhang, Wei-Ting, Duda, Dan G., Cohen, Kenneth S., Kozak, Kevin R., Cahill, Daniel P., Chen, Poe-Jou, Zhu, Mingwang, Ancukiewicz, Marek, Mrugala, Maciej M., Plotkin, Scott, Drappatz, Jan, Louis, David N., Ivy, Percy, Scadden, David T., Benner, Thomas, Loeffler, Jay S., Wen, Patrick Y., Jain, Rakesh K.
Format: Article
Language:English
Subjects:
Brain Edema - drug therapy
Brain Edema - etiology
Brain Neoplasms - blood supply
Brain Neoplasms - complications
Brain Neoplasms - drug therapy
Chemokine CXCL12
Chemokines, CXC - blood
Endothelial Cells - drug effects
Enzyme-Linked Immunosorbent Assay
Fibroblast Growth Factors - blood
Fibroblast Growth Factors - drug effects
Flow Cytometry
Glioblastoma - blood supply
Glioblastoma - complications
Glioblastoma - drug therapy
Humans
Image Processing, Computer-Assisted
Magnetic Resonance Imaging
Neoplasm Recurrence, Local - complications
Neoplasm Recurrence, Local - drug therapy
Neoplastic Cells, Circulating - drug effects
Neoplastic Stem Cells - drug effects
Neovascularization, Pathologic - drug therapy
Protein Kinase Inhibitors - therapeutic use
Quinazolines - therapeutic use
Receptors, Vascular Endothelial Growth Factor - antagonists & inhibitors
Survival Analysis
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Summary:Using MRI techniques, we show here that normalization of tumor vessels in recurrent glioblastoma patients by daily administration of AZD2171—an oral tyrosine kinase inhibitor of VEGF receptors—has rapid onset, is prolonged but reversible, and has the significant clinical benefit of alleviating edema. Reversal of normalization began by 28 days, though some features persisted for as long as four months. Basic FGF, SDF1α, and viable circulating endothelial cells (CECs) increased when tumors escaped treatment, and circulating progenitor cells (CPCs) increased when tumors progressed after drug interruption. Our study provides insight into different mechanisms of action of this class of drugs in recurrent glioblastoma patients and suggests that the timing of combination therapy may be critical for optimizing activity against this tumor.
ISSN:1535-6108
1878-3686
DOI:10.1016/j.ccr.2006.11.021