| In vitro evidence that metabolic cooperation is responsible for the bystander effect observed with HSV tk retroviral gene therapy. | |
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MedLine Citation:
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PMID: 8186287 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Tumor cells transduced with a retroviral vector expressing a herpes virus thymidine kinase (HSV tk) gene are rendered sensitive to the antiherpetic drug, ganciclovir. The bystander effect refers to the observation that not all cells need be transduced to eradicate the cell population by treatment with ganciclovir. We demonstrate that metabolic cooperation can account for this bystander effect. When HT1080 human fibrosarcoma cells marked with a lacZ gene (LZ+5) were cocultured with HT1080 cells transduced with a retrovirus expressing HSVtk (HT1080tk11), at a density at which the majority of cells were in contact, both HT1080tk11 and LZ+5 cells were killed by ganciclovir. When cells were cocultured at a low density where the majority of cells are not in contact with one another, however, only the HT1080tk11 cells were killed. This result suggests that cell contact with HT1080tk11 cells is necessary to render the HSVtk- LZ+5 cells sensitive to ganciclovir. Because involvement of metabolic cooperation in the killing of the LZ+5 cells would require not only contact between HT1080tk11 and LZ+5 cells but also the capacity to transfer small cytotoxic molecules from the former cell to the latter, transfer of radioactive molecules between the two cell lines was assessed by autoradiography after treatment of a coculture with [3H]ganciclovir. Isolated HT1080tk11 cells incorporated the labeled ganciclovir into their nuclei, whereas isolated LZ+5 cells did not. LZ+5 cells incorporated [3H]ganciclovir, only when in contact with HT1080tk11 cells. These findings indicate that a ganciclovir metabolic product, presumably a phosphorylated form, can pass from HSV tk+ to HSV tk- cells and mediate cytotoxicity as a consequence of direct contact. |
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Authors:
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W L Bi; L M Parysek; R Warnick; P J Stambrook |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
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Title: Human gene therapy Volume: 4 ISSN: 1043-0342 ISO Abbreviation: Hum. Gene Ther. Publication Date: 1993 Dec |
Date Detail:
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Created Date: 1994-06-20 Completed Date: 1994-06-20 Revised Date: 2007-11-14 |
Medline Journal Info:
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Nlm Unique ID: 9008950 Medline TA: Hum Gene Ther Country: UNITED STATES |
Other Details:
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Languages: eng Pagination: 725-31 Citation Subset: IM |
Affiliation:
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Department of Anatomy and Cell Biology, University of Cincinnati College of Medicine, OH 45267. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Base Sequence Cell Communication* Cell Count Cell Death Cell Division / drug effects Culture Media, Conditioned DNA Primers Ganciclovir / metabolism, pharmacology* Gap Junctions / metabolism Gene Therapy* Gene Transfer Techniques Genetic Vectors Humans Molecular Sequence Data Simplexvirus / enzymology* Thymidine Kinase / genetics* Tumor Cells, Cultured |
| Grant Support | |
ID/Acronym/Agency:
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ES06096/ES/NIEHS NIH HHS; NS31145/NS/NINDS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Culture Media, Conditioned; 0/DNA Primers; 82410-32-0/Ganciclovir; EC 2.7.1.21/Thymidine Kinase |
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