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

Cancer Cell. 2007 Jan;11(1):83-95. doi: 10.1016/j.ccr.2006.11.021.

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.

Publication types

  • Clinical Trial, Phase II
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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

Substances

  • CXCL12 protein, human
  • Chemokine CXCL12
  • Chemokines, CXC
  • Protein Kinase Inhibitors
  • Quinazolines
  • Fibroblast Growth Factors
  • Receptors, Vascular Endothelial Growth Factor
  • cediranib