Source:http://linkedlifedata.com/resource/pubmed/id/11859419
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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
3
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| pubmed:dateCreated |
2002-2-22
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| pubmed:abstractText |
Transcriptional targeting of gene expression has been plagued by the weakness of tissue-specific promoters. Thus, to increase promoter strength while maintaining tissue specificity, we constructed a recombinant adenovirus containing a binary promoter system with a tumor-specific promoter (CEA; carcinoembryonic antigen) driving a transcription transactivator, which then activates a minimal promoter to express a suicide gene (HSV-tk; herpes simplex virus thymidine kinase). This ADV/binary-tk induced equal or greater cell killing in a CEA-specific manner in vitro compared with the CEA-independent killing of a vector with a constitutive viral promoter driving HSV-tk (ADV/RSV-tk). To monitor adenovirus-mediated HSV-tk gene expression in vivo, we employed noninvasive nuclear imaging using a radioiodinated nucleoside analog ([((1)31)I]-FIAU) serving as a substrate for HSV-tk. [((1)31)I]-FIAU-derived radioactivity accumulated after intratumoral injection of ADV/binary-tk only in the area of CEA-positive tumors with significantly less spread to the adjacent liver tissue than after administration of the universally expressed ADV/RSV-tk. Both viruses exhibited similar antitumor efficacy upon injection of liver metastases. Importantly, in vivo dose escalation studies demonstrated significantly reduced toxicity after intravenous administration of ADV/binary-tk versus ADV/RSV-tk. In summary, the increased therapeutic index of this novel, amplified CEA-driven suicide gene therapy vector is a proof of principle for the powerful enhancement of a weak tissue-specific promoter for effective tumor restricted gene expression.
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| pubmed:grant |
http://linkedlifedata.com/resource/pubmed/grant/R01 CA-75175,
http://linkedlifedata.com/resource/pubmed/grant/R01 CA69769,
http://linkedlifedata.com/resource/pubmed/grant/R01 CA76177,
http://linkedlifedata.com/resource/pubmed/grant/R024 CA98023,
http://linkedlifedata.com/resource/pubmed/grant/R1 CA84404,
http://linkedlifedata.com/resource/pubmed/grant/R29 CA-70337
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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
|
| pubmed:month |
Feb
|
| pubmed:issn |
0969-7128
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| pubmed:author | |
| pubmed:issnType |
Print
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| pubmed:volume |
9
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| pubmed:owner |
NLM
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| pubmed:authorsComplete |
Y
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| pubmed:pagination |
168-75
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| pubmed:dateRevised |
2008-11-21
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| pubmed:meshHeading |
pubmed-meshheading:11859419-Adenoviridae,
pubmed-meshheading:11859419-Animals,
pubmed-meshheading:11859419-Breast Neoplasms,
pubmed-meshheading:11859419-Carcinoembryonic Antigen,
pubmed-meshheading:11859419-Gene Expression,
pubmed-meshheading:11859419-Gene Targeting,
pubmed-meshheading:11859419-Gene Therapy,
pubmed-meshheading:11859419-Genetic Vectors,
pubmed-meshheading:11859419-HeLa Cells,
pubmed-meshheading:11859419-Herpes Simplex Virus Protein Vmw65,
pubmed-meshheading:11859419-Humans,
pubmed-meshheading:11859419-Injections, Intralesional,
pubmed-meshheading:11859419-Liver Neoplasms,
pubmed-meshheading:11859419-Mice,
pubmed-meshheading:11859419-Mice, Inbred BALB C,
pubmed-meshheading:11859419-Promoter Regions, Genetic,
pubmed-meshheading:11859419-Retroviruses, Simian,
pubmed-meshheading:11859419-Simplexvirus,
pubmed-meshheading:11859419-Thymidine Kinase,
pubmed-meshheading:11859419-Transcription, Genetic,
pubmed-meshheading:11859419-Tumor Cells, Cultured
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| pubmed:year |
2002
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| pubmed:articleTitle |
Tumor-specific transcriptional targeting of suicide gene therapy.
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| pubmed:affiliation |
Institute for Gene Therapy and Molecular Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA.
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| pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, P.H.S.,
Research Support, U.S. Gov't, Non-P.H.S.
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