Targeting N-cadherin increases vascular permeability and differentially activates AKT in melanoma.
Journal Article (Journal Article)
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.
Full Text
Duke Authors
Cited Authors
- Turley, RS; Tokuhisa, Y; Toshimitsu, H; Lidsky, ME; Padussis, JC; Fontanella, A; Deng, W; Augustine, CK; Beasley, GM; Davies, MA; Dewhirst, MW; Tyler, DS
Published Date
- February 2015
Published In
Volume / Issue
- 261 / 2
Start / End Page
- 368 - 377
PubMed ID
- 24646553
Pubmed Central ID
- PMC4431893
Electronic International Standard Serial Number (EISSN)
- 1528-1140
Digital Object Identifier (DOI)
- 10.1097/SLA.0000000000000635
Language
- eng
Conference Location
- United States