Abstract
We previously demonstrated the importance of interleukin-8 (IL-8) as a mediator of angiogenesis, tumorigenicity, and metastasis of transitional cell carcinoma (TCC) of the bladder. In the present study, we evaluated the feasibility of adenoviral mediated antisense IL-8 gene transfer (Ad IL-8-AS) as therapy for established TCC. In vitro, Ad IL-8-AS inhibited endothelial cell proliferation and enhanced endothelial cell apoptosis. The highly metastatic human TCC cell line 253J B-V(R) was implanted into the subcutis of athymic nude mice, and intralesional therapy with Ad IL-8-AS commenced when the tumors reached a diameter between 5 and 7 mm. Tumor growth was significantly inhibited compared with therapy in controls (saline and beta-galactosidase adenovirus). Ad IL-8-AS therapy decreased the in vivo expression of IL-8 and matrix metalloproteinase type 9 (MMP-9), reduced microvessel density, and enhanced endothelial cell apoptosis. These results indicate that Ad IL-8-AS therapy targets both tumor cells and host endothelial cells resulting in endothelial cell apoptosis and significant inhibition of tumor growth.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adenoviridae / genetics*
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Animals
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Antisense Elements (Genetics) / therapeutic use*
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Apoptosis / drug effects
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Carcinoma, Transitional Cell / metabolism
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Carcinoma, Transitional Cell / pathology
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Carcinoma, Transitional Cell / therapy*
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Cell Division / drug effects
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DNA Primers / chemistry
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Endothelial Growth Factors / metabolism
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Fibroblast Growth Factor 2 / metabolism
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Fluorescent Antibody Technique
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Genetic Therapy*
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Humans
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Immunoenzyme Techniques
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In Situ Hybridization
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In Situ Nick-End Labeling
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Interleukin-8 / genetics*
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Interleukin-8 / metabolism
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Lymphokines / metabolism
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Male
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Matrix Metalloproteinase 9 / metabolism
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Mice
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Mice, Inbred BALB C
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Mice, Nude
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Platelet Endothelial Cell Adhesion Molecule-1 / analysis
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Tumor Cells, Cultured / drug effects
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Urinary Bladder Neoplasms / metabolism
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Urinary Bladder Neoplasms / pathology
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Urinary Bladder Neoplasms / therapy*
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
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beta-Galactosidase / metabolism
Substances
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Antisense Elements (Genetics)
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DNA Primers
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Endothelial Growth Factors
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Interleukin-8
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Lymphokines
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Platelet Endothelial Cell Adhesion Molecule-1
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
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Fibroblast Growth Factor 2
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beta-Galactosidase
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Matrix Metalloproteinase 9