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Targeting N-cadherin enhances antitumor activity of cytotoxic therapies in melanoma treatment.
- Source :
-
Cancer research [Cancer Res] 2008 May 15; Vol. 68 (10), pp. 3777-84. - Publication Year :
- 2008
-
Abstract
- Malignant transformation in melanoma is characterized by a phenotype "switch" from E- to N-cadherin, which is associated with increased motility and invasiveness of the tumor and altered signaling, leading to decreased apoptosis. We hypothesized that the novel pentapeptide (ADH-1), which disrupts N-cadherin adhesion, could sensitize melanoma tumors to the cytotoxic effects of chemotherapy. N-cadherin-expressing human melanoma-derived cell lines were used to generate xenografts in animal models to study isolated limb infusion with melphalan and systemic chemotherapy with temozolomide. We report here that melphalan in combination with ADH-1 significantly reduced tumor growth up to 30-fold over melphalan alone. ADH-1 enhancement of response to melphalan was associated with increased formation of DNA adducts, increased apoptosis, and intracellular signaling changes associated with focal adhesions and fibroblast growth factor receptors. Targeted therapy using an N-cadherin antagonist can dramatically augment the antitumor effects of chemotherapy and is a novel approach to optimizing treatment for melanoma.
- Subjects :
- Animals
Cadherins chemistry
DNA Adducts chemistry
Dacarbazine analogs & derivatives
Dacarbazine pharmacology
Humans
Immunotherapy methods
Melanoma metabolism
Melphalan pharmacology
Models, Biological
Neoplasm Transplantation
Phenotype
Rats
Rats, Nude
Temozolomide
Antineoplastic Agents, Alkylating pharmacology
Cadherins metabolism
Melanoma drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1538-7445
- Volume :
- 68
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Cancer research
- Publication Type :
- Academic Journal
- Accession number :
- 18483261
- Full Text :
- https://doi.org/10.1158/0008-5472.CAN-07-5949