Source:http://linkedlifedata.com/resource/pubmed/id/15904470
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Predicate | Object |
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rdf:type | |
lifeskim:mentions | |
pubmed:issue |
5
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pubmed:dateCreated |
2005-5-20
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pubmed:abstractText |
Hypoxia-inducible factors, key transcription factors for hypoxia-dependent gene expression, play important roles in angiogenesis and tumor growth. The VHL protein binds to the alpha subunit of (HIF-alpha) for its oxygen-dependent degradation. VHL mutations are found frequently in sporadic RCC. Disruption of VHL results in an abnormal accumulation of HIF-alpha, leading to the upregulation of downstream genes such as the vascular endothelial growth factor gene. We constructed a luciferase reporter vector driven by hypoxia-responsive elements (5HRE/luc) and a therapeutic vector expressing a herpes simplex virus thymidine kinase gene (5HRE/tk). In the transient transfection assay using VHL-deficient 786-O cells, constitutive luciferase expression was detected under both aerobic and hypoxic conditions. In contrast, 786-O cells transfected with a wild-type VHL showed hypoxia-inducible luciferase activity. In in vitro MTS assay, 50% of growth inhibition of 786-O cells stably transfected with 5HRE/tk was achieved with exposure to 0.2 microg/mL of GCV under both aerobic and hypoxic conditions. Xenografts of the stable clone in SCID mice exhibited a marked regression on daily injections of GCV (50 mg/kg) for 10 days. In conclusion, a hypoxia-responsive vector may have therapeutic potential for RCC with VHL mutations.
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pubmed:language |
eng
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pubmed:journal | |
pubmed:citationSubset |
IM
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pubmed:chemical | |
pubmed:status |
MEDLINE
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pubmed:month |
May
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pubmed:issn |
1347-9032
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pubmed:author | |
pubmed:issnType |
Print
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pubmed:volume |
96
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
288-94
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pubmed:dateRevised |
2006-11-15
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pubmed:meshHeading |
pubmed-meshheading:15904470-Animals,
pubmed-meshheading:15904470-Carcinoma, Renal Cell,
pubmed-meshheading:15904470-Cell Line, Tumor,
pubmed-meshheading:15904470-Gene Therapy,
pubmed-meshheading:15904470-Genes, Reporter,
pubmed-meshheading:15904470-Genetic Vectors,
pubmed-meshheading:15904470-Humans,
pubmed-meshheading:15904470-Mice,
pubmed-meshheading:15904470-Mice, SCID,
pubmed-meshheading:15904470-Mutation,
pubmed-meshheading:15904470-Protein Subunits,
pubmed-meshheading:15904470-Response Elements,
pubmed-meshheading:15904470-Signal Transduction,
pubmed-meshheading:15904470-Substrate Specificity,
pubmed-meshheading:15904470-Thymidine Kinase,
pubmed-meshheading:15904470-Transcription Factors,
pubmed-meshheading:15904470-Tumor Suppressor Proteins,
pubmed-meshheading:15904470-Xenograft Model Antitumor Assays
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pubmed:year |
2005
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pubmed:articleTitle |
A tumor-specific gene therapy strategy targeting dysregulation of the VHL/HIF pathway in renal cell carcinomas.
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pubmed:affiliation |
Department of Therapeutic Radiology and Oncology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto 606-8507, Japan.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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