title: Bevacizumab-induced transient remodeling of the vasculature in neuroblastoma xenografts results in improved delivery and efficacy of systemically administered chemotherapy.
abstract: OBJECTIVE
  Dysfunctional tumor vessels can be a significant barrier to effective cancer therapy. However, increasing evidence suggests that vascular endothelial growth factor (VEGF) inhibition can effect transient "normalization" of the tumor vasculature, thereby improving tumor perfusion and, consequently, delivery of systemic chemotherapy. We sought to examine temporal changes in tumor vascular function in response to the anti-VEGF antibody, bevacizumab.
  
  
  METHODS
  Established orthotopic neuroblastoma xenografts treated with bevacizumab were evaluated at serial time points for treatment-associated changes in intratumoral vascular physiology, penetration of systemically administered chemotherapy, and efficacy of combination therapy.
  
  
  RESULTS
  After a single bevacizumab dose, a progressive decrease in tumor microvessel density to <30% of control was observed within 7 days. Assessment of the tumor microenvironment revealed a rapid, sustained decrease in both tumor vessel permeability and tumor interstitial fluid pressure, whereas intratumoral perfusion, as assessed by contrast-enhanced ultrasonography, was improved, although this latter change abated by 1 week. Intratumoral drug delivery mirrored these changes; penetration of chemotherapy was improved by as much as 81% when given 1 to 3 days after bevacizumab, compared with when both drugs were given concomitantly, or 7 days apart. Finally, administering topotecan to tumor-bearing mice 3 days after bevacizumab resulted in greater tumor growth inhibition (36% of control size) than with monotherapy (88% bevacizumab, 54% topotecan) or concomitant administration of the two drugs (44%).
  
  
  CONCLUSIONS
  Bevacizumab-mediated VEGF blockade effects alterations in tumor vessel physiology that allow improved delivery and efficacy of chemotherapy, although careful consideration of drug scheduling is required to optimize antitumor activity.
authors.affiliation: Department of Surgery, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Paxton V
authors.initials: PV
authors.lastname: Dickson
authors.forename: John B
authors.initials: JB
authors.lastname: Hamner
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Sims
authors.forename: Charles H
authors.initials: CH
authors.lastname: Fraga
authors.forename: Catherine Y C
authors.initials: CY
authors.lastname: Ng
authors.forename: Surender
authors.initials: S
authors.lastname: Rajasekeran
authors.forename: Nikolaus L
authors.initials: NL
authors.lastname: Hagedorn
authors.forename: M Beth
authors.initials: MB
authors.lastname: McCarville
authors.forename: Clinton F
authors.initials: CF
authors.lastname: Stewart
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Davidoff
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology*; D000068258:Bevacizumab; D045744:Cell Line, Tumor; D006801:Humans; D008297:Male; D051379:Mice; D008833:Microcirculation; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D009447:Neuroblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D011312:Pressure; D042461:Vascular Endothelial Growth Factor A / Q000737:chemistry / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab