title: Bevacizumab-induced alterations in vascular permeability and drug delivery: a novel approach to augment regional chemotherapy for in-transit melanoma.
abstract: OBJECTIVE
  To investigate whether the systemically administered anti-VEGF monoclonal antibody bevacizumab could improve regional chemotherapy treatment of advanced extremity melanoma by enhancing delivery and tumor uptake of regionally infused melphalan (LPAM).
  
  
  METHODS
  After treatment with systemic bevacizumab or saline, changes in vascular permeability were determined by spectrophotometric analysis of tumors infused with Evan's blue dye. Changes in vascular structure and tumor hemoglobin-oxygen saturation HbO(2) were determined by intravital microscopy and diffuse reflectance spectroscopy, respectively. Rats bearing the low-VEGF secreting DM738 and the high-VEGF secreting DM443 melanoma xenografts underwent isolated limb infusion (ILI) with melphalan (LPAM) or saline via the femoral vessels. The effect of bevacizumab on terminal drug delivery was determined by immunohistochemical analysis of LPAM-DNA adducts in tumor tissues.
  
  
  RESULTS
  Single-dose bevacizumab given three days before ILI with LPAM significantly decreased vascular permeability (50.3% in DM443, P < 0.01 and 35% in DM738, P < 0.01) and interstitial fluid pressure (57% in DM443, P < 0.01 and 50% in DM738, P = 0.01). HbO(2) decreased from baseline in mice following treatment with bevacizumab. Systemic bevacizumab significantly enhanced tumor response to ILI with LPAM in two melanoma xenografts, DM443 and DM738, increasing quadrupling time 37% and 113%, respectively (P = 0.03). Immunohistochemical analyses of tumor specimens showed that pretreatment with systemic bevacizumab markedly increased LPAM-DNA adduct formation.
  
  
  CONCLUSIONS
  Systemic treatment with bevacizumab before regional chemotherapy increases delivery of LPAM to tumor cells and represents a novel way to augment response to regional therapy for advanced extremity melanoma.
authors.affiliation: Department of Surgery, Duke University, and Durham VA Medical Center, Durham, North Carolina 27710, USA. ryan.turley@duke.edu
authors.forename: Ryan S
authors.initials: RS
authors.lastname: Turley
authors.forename: Andrew N
authors.initials: AN
authors.lastname: Fontanella
authors.forename: James C
authors.initials: JC
authors.lastname: Padussis
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Toshimitsu
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Tokuhisa
authors.forename: Eugenia H
authors.initials: EH
authors.lastname: Cho
authors.forename: Gabi
authors.initials: G
authors.lastname: Hanna
authors.forename: Georgia M
authors.initials: GM
authors.lastname: Beasley
authors.forename: Christina K
authors.initials: CK
authors.lastname: Augustine
authors.forename: Mark W
authors.initials: MW
authors.lastname: Dewhirst
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Tyler
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D000068258:Bevacizumab; D002199:Capillary Permeability / Q000187:drug effects*; D045744:Cell Line, Tumor; D010478:Chemotherapy, Cancer, Regional Perfusion; D016503:Drug Delivery Systems; D005260:Female; D006801:Humans; D008545:Melanoma / Q000188:drug therapy*; D008558:Melphalan / Q000008:administration & dosage* / Q000627:therapeutic use; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D011923:Rats, Nude; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; D008558:Melphalan