title: Bevacizumab has differential and dose-dependent effects on glioma blood vessels and tumor cells.
abstract: OBJECTIVE
  Bevacizumab targets VEGF-A and has proved beneficial in glioma patients, improving clinical symptoms by the reduction of tumor edema. However, it remains controversial whether or not bevacizumab exerts antitumor effects in addition to (and potentially independent of) its effects on tumor vessels, and it is unknown what doses are needed to achieve this.
  
  
  METHODS
  We established a novel orthotopic glioma mouse model that allowed us to simultaneously study the kinetics of the morphologic and functional vascular changes, tumor growth, and the viability of individual tumor cells during the course of anti-VEGF therapy in the same microscopic tumor region in real-time. Three doses of bevacizumab were compared, a subclinical dose and two clinical doses (medium and high).
  
  
  RESULTS
  Low (subclinical) doses of bevacizumab led to a significant reduction of the total vascular volume without affecting tumor cell viability or the overall tumor growth rates. Medium and high doses triggered a similar degree of vascular regression but significantly decreased tumor growth and prolonged survival. Remaining vessels revealed morphologic features of vascular normalization, reduced permeability, and an increase in blood flow velocity; the latter was dose dependent. We observed an uncoupling of the antitumoral and the antivascular effects of bevacizumab with the high dose only, which showed the potential to cause microregional glioma cell regression. In some tumor regions, pronounced glioma cell regression occurred even without vascular regression. In vitro, there was no effect of bevacizumab on glioma cell proliferation.
  
  
  CONCLUSIONS
  Regression of glioma cells can occur independently from vascular regression, suggesting that high doses of bevacizumab have indirect anticancer cell properties in vivo.
authors.affiliation: Department of Neurology, University Hospital, Ludwig-Maximilians University, Munich, Germany.
authors.forename: Louisa
authors.initials: L
authors.lastname: von Baumgarten
authors.forename: David
authors.initials: D
authors.lastname: Brucker
authors.forename: Anca
authors.initials: A
authors.lastname: Tirniceru
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Kienast
authors.forename: Stefan
authors.initials: S
authors.lastname: Grau
authors.forename: Steffen
authors.initials: S
authors.lastname: Burgold
authors.forename: Jochen
authors.initials: J
authors.lastname: Herms
authors.forename: Frank
authors.initials: F
authors.lastname: Winkler
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage*; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage*; D000068258:Bevacizumab; D001932:Brain Neoplasms / Q000098:blood supply* / Q000188:drug therapy* / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D005909:Glioblastoma / Q000098:blood supply* / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000517:prevention & control; D016019:Survival Analysis
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab