The Extent of Heterocellular Communication Mediated by Gap Junctions is Predictive of Bystander Tumor Cytotoxicity in vitro
Herpes simplex virus thymidine kinase (HSV-tk)/ganciclovir (GCV) viral-directed enzyme prodrug gene therapy causes potent, tumor-selective cytotoxicity in animal models in which HSV-tk gene transduction is limited to a minority of tumor cells. The passage of toxic molecules from HSV-tk+cells to neig...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 1995-11, Vol.92 (24), p.11071-11075 |
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| container_issue | 24 |
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| container_title | Proceedings of the National Academy of Sciences - PNAS |
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| creator | Fick, James Barker, Fred G. Dazin, Paul Westphale, Eileen M. Beyer, Eric C. Israel, Mark A. |
| description | Herpes simplex virus thymidine kinase (HSV-tk)/ganciclovir (GCV) viral-directed enzyme prodrug gene therapy causes potent, tumor-selective cytotoxicity in animal models in which HSV-tk gene transduction is limited to a minority of tumor cells. The passage of toxic molecules from HSV-tk+cells to neighboring HSV-tk-cells during GCV therapy is one mechanism that may account for this "bystander" cytotoxicity. To investigate whether gap junction-mediated intercellular coupling could mediate this bystander effect, we used a flow cytometry assay to quantitate the extent of heterocellular coupling between HSV-tk+murine fibroblasts and both rodent and human tumor cell lines. Bystander tumor cytotoxicity during GCV treatment in a coculture assay was highly correlated (P < 0.001) with the extent of gap junction-mediated coupling. These findings show that gap junction-mediated intercellular coupling contributes to the in vitro bystander effect during HSV-tk/GCV therapy and that retroviral transduction of tumor cells is not required for bystander cytotoxicity. |
| doi_str_mv | 10.1073/pnas.92.24.11071 |
| format | Article |
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The passage of toxic molecules from HSV-tk+cells to neighboring HSV-tk-cells during GCV therapy is one mechanism that may account for this "bystander" cytotoxicity. To investigate whether gap junction-mediated intercellular coupling could mediate this bystander effect, we used a flow cytometry assay to quantitate the extent of heterocellular coupling between HSV-tk+murine fibroblasts and both rodent and human tumor cell lines. Bystander tumor cytotoxicity during GCV treatment in a coculture assay was highly correlated (P < 0.001) with the extent of gap junction-mediated coupling. 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The passage of toxic molecules from HSV-tk+cells to neighboring HSV-tk-cells during GCV therapy is one mechanism that may account for this "bystander" cytotoxicity. To investigate whether gap junction-mediated intercellular coupling could mediate this bystander effect, we used a flow cytometry assay to quantitate the extent of heterocellular coupling between HSV-tk+murine fibroblasts and both rodent and human tumor cell lines. Bystander tumor cytotoxicity during GCV treatment in a coculture assay was highly correlated (P < 0.001) with the extent of gap junction-mediated coupling. These findings show that gap junction-mediated intercellular coupling contributes to the in vitro bystander effect during HSV-tk/GCV therapy and that retroviral transduction of tumor cells is not required for bystander cytotoxicity.</description><subject>3T3 cells</subject><subject>Animals</subject><subject>Antimetabolites - toxicity</subject><subject>Antineoplastic Agents - toxicity</subject><subject>Cell Communication</subject><subject>Cell cycle</subject><subject>Cell Cycle - drug effects</subject><subject>Cell lines</subject><subject>Cell Survival - drug effects</subject><subject>Cells</subject><subject>Coculture techniques</subject><subject>Cytotoxicity</subject><subject>Endothelial cells</subject><subject>Fibroblasts</subject><subject>Ganciclovir - administration & dosage</subject><subject>Ganciclovir - toxicity</subject><subject>Gap Junctions - physiology</subject><subject>herpes simplex virus</subject><subject>Humans</subject><subject>Mice</subject><subject>Prodrugs - administration & dosage</subject><subject>Rats</subject><subject>Simplexvirus - enzymology</subject><subject>Thymidine Kinase - administration & dosage</subject><subject>Tumor cell line</subject><subject>Tumor Cells, Cultured</subject><subject>Tumors</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1995</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kcFv0zAYxS0EGmVw5wDCJ8Ql5bPjxLXEBaqxgYbgUM6Wk3xhnpK42E7VaP_8HFoqduFk2e_33mf7EfKSwZKBzN9vBxOWii-5WLJ0wB6RBQPFslIoeEwWAFxmK8HFU_IshFsAUMUKzsiZFFKpXC3I3eYG6cU-4hCpa-kVRvSuxq4bO-Pp2vX9ONjaROsG-g0bayI2tJropdnSr-NQz0KgNtAfPqlpu8M559MUohka9HQz9i4FTdFFt7e1jRO1A93Z6N1z8qQ1XcAXx_Wc_Px8sVlfZdffL7-sP15ndVGKmLGyqEzDgFcFiBJQNMagqEFBqYSsW2C1qRqhpGgNV4xxEC0CtpWQIIsV5ufkwyF3O1Y9NnV6qzed3nrbGz9pZ6x-qAz2Rv9yOy2gkHmyvz3avfs9Yoi6t2H-IjOgG4NmpVpJVcwgHMDauxA8tqcRDPRcl57r0oprLvSfupLl9b9XOxmO_ST9zVGfnX_Vhwnv_k_oduy6iPuY0FcH9DZE508sz8tVmpffA5Bmtno</recordid><startdate>19951121</startdate><enddate>19951121</enddate><creator>Fick, James</creator><creator>Barker, Fred G.</creator><creator>Dazin, Paul</creator><creator>Westphale, Eileen M.</creator><creator>Beyer, Eric C.</creator><creator>Israel, Mark A.</creator><general>National Academy of Sciences of the United States of America</general><general>National Acad Sciences</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QO</scope><scope>7U7</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>P64</scope><scope>5PM</scope></search><sort><creationdate>19951121</creationdate><title>The Extent of Heterocellular Communication Mediated by Gap Junctions is Predictive of Bystander Tumor Cytotoxicity in vitro</title><author>Fick, James ; 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| ispartof | Proceedings of the National Academy of Sciences - PNAS, 1995-11, Vol.92 (24), p.11071-11075 |
| issn | 0027-8424 1091-6490 |
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| source | MEDLINE; JSTOR Archive Collection A-Z Listing; PubMed Central; Alma/SFX Local Collection; Free Full-Text Journals in Chemistry |
| subjects | 3T3 cells Animals Antimetabolites - toxicity Antineoplastic Agents - toxicity Cell Communication Cell cycle Cell Cycle - drug effects Cell lines Cell Survival - drug effects Cells Coculture techniques Cytotoxicity Endothelial cells Fibroblasts Ganciclovir - administration & dosage Ganciclovir - toxicity Gap Junctions - physiology herpes simplex virus Humans Mice Prodrugs - administration & dosage Rats Simplexvirus - enzymology Thymidine Kinase - administration & dosage Tumor cell line Tumor Cells, Cultured Tumors |
| title | The Extent of Heterocellular Communication Mediated by Gap Junctions is Predictive of Bystander Tumor Cytotoxicity in vitro |
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