title: AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients.
abstract: 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, SDF1alpha, 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.
authors.affiliation: Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. tbatchelor@partners.org
authors.forename: Tracy T
authors.initials: TT
authors.lastname: Batchelor
authors.forename: A Gregory
authors.initials: AG
authors.lastname: Sorensen
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: di Tomaso
authors.forename: Wei-Ting
authors.initials: WT
authors.lastname: Zhang
authors.forename: Dan G
authors.initials: DG
authors.lastname: Duda
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Cohen
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Kozak
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Cahill
authors.forename: Poe-Jou
authors.initials: PJ
authors.lastname: Chen
authors.forename: Mingwang
authors.initials: M
authors.lastname: Zhu
authors.forename: Marek
authors.initials: M
authors.lastname: Ancukiewicz
authors.forename: Maciej M
authors.initials: MM
authors.lastname: Mrugala
authors.forename: Scott
authors.initials: S
authors.lastname: Plotkin
authors.forename: Jan
authors.initials: J
authors.lastname: Drappatz
authors.forename: David N
authors.initials: DN
authors.lastname: Louis
authors.forename: Percy
authors.initials: P
authors.lastname: Ivy
authors.forename: David T
authors.initials: DT
authors.lastname: Scadden
authors.forename: Thomas
authors.initials: T
authors.lastname: Benner
authors.forename: Jay S
authors.initials: JS
authors.lastname: Loeffler
authors.forename: Patrick Y
authors.initials: PY
authors.lastname: Wen
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Jain
mesh_terms: D001929:Brain Edema / Q000188:drug therapy* / Q000209:etiology; D001932:Brain Neoplasms / Q000098:blood supply / Q000150:complications / Q000188:drug therapy*; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000097:blood; D042783:Endothelial Cells / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D005346:Fibroblast Growth Factors / Q000097:blood / Q000187:drug effects; D005434:Flow Cytometry; D005909:Glioblastoma / Q000098:blood supply / Q000150:complications / Q000188:drug therapy*; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging; D009364:Neoplasm Recurrence, Local / Q000150:complications / Q000188:drug therapy; D009360:Neoplastic Cells, Circulating / Q000187:drug effects; D014411:Neoplastic Stem Cells / Q000187:drug effects; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011799:Quinazolines / Q000627:therapeutic use*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors; D016019:Survival Analysis; D007211:Indoles
chemical_list: D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D005346:Fibroblast Growth Factors; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D040262:Receptors, Vascular Endothelial Growth Factor; C515255:CXCL12 protein, human; C500926:cediranib; D007211:Indoles