AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients

作     者：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. 

作者机构：Massachusetts Gen Hosp Dept Neurol Boston MA 02114 USA Massachusetts Gen Hosp Dept Radiat Oncol Boston MA 02114 USA Massachusetts Gen Hosp Dept Radiol Boston MA 02114 USA Massachusetts Gen Hosp Ctr Regenerat Med Boston MA 02114 USA Massachusetts Gen Hosp Dept Pathol Boston MA 02114 USA Harvard Univ Sch Med Boston MA 02114 USA Massachusetts Gen Hosp HST AA Martinos Ctr Biomed Imaging Boston MA 02114 USA Harvard Univ Sch Med Div Hlth Sci & Technol Boston MA 02114 USA MIT Dept Nucl Sci & Engn Cambridge MA 02139 USA Childrens Hosp Dana Farber Canc Inst Dept Adult Oncol Boston MA 02115 USA NCI Canc Therapy Evaluat Program Bethesda MD 20892 USA 

出 版 物：《CANCER CELL》 (癌细胞)

年 卷 期：2007年第11卷第1期

页      面：83-95页

核心收录：

学科分类：0710[理学-生物学] 1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学] 

基　　金：NCI NIH HHS [R01CA115767, R01CA57683, P01 CA080124, R01 CA057683, R21CA117079, P01CA80124, R01 CA115767-03, R21 CA117079, R01 CA115767, P01 CA080124-08, R01 CA057683-15, R21 CA117079-02] Funding Source: Medline NCRR NIH HHS [P41 RR014075-10, M01 RR001066, M01 RR001066-26, P41 RR014075, P41-RR14075, M01-RR-01066] Funding Source: Medline 

主　　题：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 Enzyme-Linked Immunosorbent Assay Fibroblast Growth Factors/blood Fibroblast Growth Factors/drug effects Flow Cytometry 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 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 

摘      要：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, SDF1 alpha, 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.