title: Targeting N-cadherin increases vascular permeability and differentially activates AKT in melanoma.
abstract: OBJECTIVE
  We investigate the mechanism through which N-cadherin disruption alters the effectiveness of regional chemotherapy for locally advanced melanoma.
  
  
  BACKGROUND
  N-cadherin antagonism during regional chemotherapy has demonstrated variable treatment effects.
  
  
  METHODS
  Isolated limb infusion (ILI) with melphalan (LPAM) or temozolomide (TMZ) was performed on rats bearing melanoma xenografts after systemic administration of the N-cadherin antagonist, ADH-1, or saline. Permeability studies were performed using Evans blue dye as the infusate, and interstitial fluid pressure was measured. Immunohistochemistry of LPAM-DNA adducts and damage was performed as surrogates for LPAM and TMZ delivery. Tumor signaling was studied by Western blotting and reverse-phase protein array analysis.
  
  
  RESULTS
  Systemic ADH-1 was associated with increased growth and activation of the PI3K (phosphatidylinositol-3 kinase)-AKT pathway in A375 but not DM443 xenografts. ADH-1 in combination with LPAM ILI improved antitumor responses compared with LPAM alone in both cell lines. Combination of ADH-1 with TMZ ILI did not improve tumor response in A375 tumors. ADH-1 increased vascular permeability without effecting tumor interstitial fluid pressure, leading to increased delivery of LPAM but not TMZ.
  
  
  CONCLUSIONS
  ADH-1 improved responses to regional LPAM but had variable effects on tumors regionally treated with TMZ. N-cadherin-targeting agents may lead to differential effects on the AKT signaling axis that can augment growth of some tumors. The vascular targeting actions of N-cadherin antagonism may not augment some regionally delivered alkylating agents, leading to a net increase in tumor size with this type of combination treatment strategy.
authors.affiliation: Departments of *Surgery †Radiation Oncology and Biomedical Engineering, Duke University, Durham, NC; and ‡Departments of Melanoma Medical Oncology and Systems Biology, University of Texas M.D. Anderson Cancer Center, Houston, TX.
authors.forename: Ryan S
authors.initials: RS
authors.lastname: Turley
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Tokuhisa
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Toshimitsu
authors.forename: Michael E
authors.initials: ME
authors.lastname: Lidsky
authors.forename: James C
authors.initials: JC
authors.lastname: Padussis
authors.forename: Andrew
authors.initials: A
authors.lastname: Fontanella
authors.forename: Wanleng
authors.initials: W
authors.lastname: Deng
authors.forename: Christina K
authors.initials: CK
authors.lastname: Augustine
authors.forename: Georgia M
authors.initials: GM
authors.lastname: Beasley
authors.forename: Michael A
authors.initials: MA
authors.lastname: Davies
authors.forename: Mark W
authors.initials: MW
authors.lastname: Dewhirst
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Tyler
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000378:metabolism*; D015153:Blotting, Western; D015820:Cadherins / Q000037:antagonists & inhibitors; D002199:Capillary Permeability / Q000187:drug effects*; D045744:Cell Line, Tumor; D010478:Chemotherapy, Cancer, Regional Perfusion; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D008558:Melphalan / Q000494:pharmacology / Q000627:therapeutic use; D009368:Neoplasm Transplantation; D009842:Oligopeptides / Q000494:pharmacology* / Q000627:therapeutic use; D010456:Peptides, Cyclic / Q000494:pharmacology* / Q000627:therapeutic use; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D040081:Protein Array Analysis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D011923:Rats, Nude; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D000077204:Temozolomide
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D015820:Cadherins; D003606:Dacarbazine; D008558:Melphalan; D009842:Oligopeptides; D010456:Peptides, Cyclic; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D000077204:Temozolomide; C518575:ADH-1 pepide