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The tumor microenvironment expression of p-STAT3 influences the efficacy of cyclophosphamide with WP1066 in murine melanoma models
- Publication Year :
- 2011
-
Abstract
- Melanoma is a common and deadly tumor that upon metastasis to the central nervous system (CNS) has median survival duration of less than 5 months. Activation of the signal transducer and activator of transcription 3 (STAT3) has been identified as a key mediator that drives the fundamental components of melanoma. We hypothesized that WP1066, a novel inhibitor of STAT3 signaling, would enhance the antitumor activity of cyclophosphamide (CTX) against melanoma, including disease within the CNS. The mechanisms of efficacy were investigated by tumor- and immune-mediated cytotoxic assays, in vivo evaluation of the reduction of regulatory T cells (Tregs) and by determining intratumoral p-STAT3 expression by immunohistochemistry. Combinational therapy of WP1066, with both metronomic and cytotoxic dosing of CTX, was investigated in a model system of systemic and intracerebral melanoma in syngeneic mice. Inhibition of p-STAT3 by WP1066 was enhanced with CTX in a dose-dependent manner. However, in mice with intracerebral melanoma, the greatest therapeutic benefit was seen in animals treated with cytotoxic CTX dosing and WP1066, whose median survival time was 120 days, an increase of 375%, with 57% long-term survivors. This treatment efficacy correlated with p-STAT3 expression levels within the tumor microenvironment. The efficacy of the combination of cytotoxic dosing of CTX with WP1066 is attributed to the direct tumor cytotoxic effects of the agents and has the greatest therapeutic potential for the treatment of CNS melanoma.
- Subjects :
- STAT3 Transcription Factor
Cancer Research
Cyclophosphamide
Pyridines
Melanoma, Experimental
T-Lymphocytes, Regulatory
Article
Metastasis
Mice
In vivo
Cell Line, Tumor
Antineoplastic Combined Chemotherapy Protocols
medicine
Tumor Microenvironment
Cytotoxic T cell
Animals
STAT3
Tumor microenvironment
biology
business.industry
Brain Neoplasms
Melanoma
Tyrphostins
medicine.disease
Mice, Inbred C57BL
Disease Models, Animal
Oncology
Immunology
Administration, Metronomic
STAT protein
Cancer research
biology.protein
Female
business
medicine.drug
Signal Transduction
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....a7391ff02c210891bcb49948b78c9d56