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Targeting N-cadherin increases vascular permeability and differentially activates AKT in melanoma.

Publication ,  Journal Article
Turley, RS; Tokuhisa, Y; Toshimitsu, H; Lidsky, ME; Padussis, JC; Fontanella, A; Deng, W; Augustine, CK; Beasley, GM; Davies, MA; Dewhirst, MW ...
Published in: Ann Surg
February 2015

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.

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Published In

Ann Surg

DOI

EISSN

1528-1140

Publication Date

February 2015

Volume

261

Issue

2

Start / End Page

368 / 377

Location

United States

Related Subject Headings

  • Temozolomide
  • Surgery
  • Skin Neoplasms
  • Reverse Transcriptase Polymerase Chain Reaction
  • Real-Time Polymerase Chain Reaction
  • Rats, Nude
  • Rats
  • Proto-Oncogene Proteins c-akt
  • Protein Array Analysis
  • Phosphatidylinositol 3-Kinases
 

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Turley, R. S., Tokuhisa, Y., Toshimitsu, H., Lidsky, M. E., Padussis, J. C., Fontanella, A., … Tyler, D. S. (2015). Targeting N-cadherin increases vascular permeability and differentially activates AKT in melanoma. Ann Surg, 261(2), 368–377. https://doi.org/10.1097/SLA.0000000000000635
Turley, Ryan S., Yoshihiro Tokuhisa, Hiroaki Toshimitsu, Michael E. Lidsky, James C. Padussis, Andrew Fontanella, Wanleng Deng, et al. “Targeting N-cadherin increases vascular permeability and differentially activates AKT in melanoma.Ann Surg 261, no. 2 (February 2015): 368–77. https://doi.org/10.1097/SLA.0000000000000635.
Turley RS, Tokuhisa Y, Toshimitsu H, Lidsky ME, Padussis JC, Fontanella A, et al. Targeting N-cadherin increases vascular permeability and differentially activates AKT in melanoma. Ann Surg. 2015 Feb;261(2):368–77.
Turley, Ryan S., et al. “Targeting N-cadherin increases vascular permeability and differentially activates AKT in melanoma.Ann Surg, vol. 261, no. 2, Feb. 2015, pp. 368–77. Pubmed, doi:10.1097/SLA.0000000000000635.
Turley RS, Tokuhisa Y, Toshimitsu H, Lidsky ME, Padussis JC, Fontanella A, Deng W, Augustine CK, Beasley GM, Davies MA, Dewhirst MW, Tyler DS. Targeting N-cadherin increases vascular permeability and differentially activates AKT in melanoma. Ann Surg. 2015 Feb;261(2):368–377.

Published In

Ann Surg

DOI

EISSN

1528-1140

Publication Date

February 2015

Volume

261

Issue

2

Start / End Page

368 / 377

Location

United States

Related Subject Headings

  • Temozolomide
  • Surgery
  • Skin Neoplasms
  • Reverse Transcriptase Polymerase Chain Reaction
  • Real-Time Polymerase Chain Reaction
  • Rats, Nude
  • Rats
  • Proto-Oncogene Proteins c-akt
  • Protein Array Analysis
  • Phosphatidylinositol 3-Kinases