Assessing and Overcoming Resistance Phenomena against a Genetically Modified Vaccinia Virus in Selected Cancer Cell Lines
Genetically modified vaccinia viruses (VACVs) have been shown to possess profound oncolytic capabilities. However, tumor cell resistance to VACVs may endanger broad clinical success. Using cell mass assays, viral replication studies, and fluorescence microscopy, we investigated primary resistance ph...
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-10-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/21/20/7618 |
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| author | Susanne Berchtold Julia Beil Christian Raff Irina Smirnow Martina Schell Janina D’Alvise Silvia Gross Ulrich M. Lauer |
| author_facet | Susanne Berchtold Julia Beil Christian Raff Irina Smirnow Martina Schell Janina D’Alvise Silvia Gross Ulrich M. Lauer |
| author_sort | Susanne Berchtold |
| collection | DOAJ |
| description | Genetically modified vaccinia viruses (VACVs) have been shown to possess profound oncolytic capabilities. However, tumor cell resistance to VACVs may endanger broad clinical success. Using cell mass assays, viral replication studies, and fluorescence microscopy, we investigated primary resistance phenomena of cell lines of the NCI-60 tumor cell panel to GLV-1h94, a derivative of the <i>Lister</i> strain of VACV, which encodes the enzyme super cytosine deaminase (SCD) that converts the prodrug 5-fluorocytosine (5-FC) into the chemotherapeutic compound 5-fluorouracil (5-FU). After treatment with GLV-1h94 alone, only half of the cell lines were defined as highly susceptible to GLV-1h94-induced oncolysis. When adding 5-FC, 85% of the cell lines became highly susceptible to combinatorial treatment; none of the tested tumor cell lines exhibited a “high-grade resistance” pattern. Detailed investigation of the SCD prodrug system suggested that the cytotoxic effect of converted 5-FU is directed either against the cells or against the virus particles, depending on the balance between cell line-specific susceptibility to GLV-1h94-induced oncolysis and 5-FU sensitivity. The data provided by this work underline that cellular resistance against VACV-based virotherapy can be overcome by virus-encoded prodrug systems. Phase I/II clinical trials are recommended to further elucidate the enormous potential of this combination therapy. |
| first_indexed | 2024-03-10T15:36:52Z |
| format | Article |
| id | doaj.art-d1ea0023af6f41cc91f7f316498dab5c |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T15:36:52Z |
| publishDate | 2020-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-d1ea0023af6f41cc91f7f316498dab5c2023-11-20T17:09:51ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-10-012120761810.3390/ijms21207618Assessing and Overcoming Resistance Phenomena against a Genetically Modified Vaccinia Virus in Selected Cancer Cell LinesSusanne Berchtold0Julia Beil1Christian Raff2Irina Smirnow3Martina Schell4Janina D’Alvise5Silvia Gross6Ulrich M. Lauer7Department of Internal Medicine VIII, University Hospital Tübingen, D-72076 Tübingen, GermanyDepartment of Internal Medicine VIII, University Hospital Tübingen, D-72076 Tübingen, GermanyDepartment of Internal Medicine VIII, University Hospital Tübingen, D-72076 Tübingen, GermanyDepartment of Internal Medicine VIII, University Hospital Tübingen, D-72076 Tübingen, GermanyDepartment of Internal Medicine VIII, University Hospital Tübingen, D-72076 Tübingen, GermanyCore Facility for Medical Bioanalytics, Institute for Ophthalmic Research, University Hospital Tübingen, D-72076 Tübingen, GermanyDepartment of Internal Medicine VIII, University Hospital Tübingen, D-72076 Tübingen, GermanyDepartment of Internal Medicine VIII, University Hospital Tübingen, D-72076 Tübingen, GermanyGenetically modified vaccinia viruses (VACVs) have been shown to possess profound oncolytic capabilities. However, tumor cell resistance to VACVs may endanger broad clinical success. Using cell mass assays, viral replication studies, and fluorescence microscopy, we investigated primary resistance phenomena of cell lines of the NCI-60 tumor cell panel to GLV-1h94, a derivative of the <i>Lister</i> strain of VACV, which encodes the enzyme super cytosine deaminase (SCD) that converts the prodrug 5-fluorocytosine (5-FC) into the chemotherapeutic compound 5-fluorouracil (5-FU). After treatment with GLV-1h94 alone, only half of the cell lines were defined as highly susceptible to GLV-1h94-induced oncolysis. When adding 5-FC, 85% of the cell lines became highly susceptible to combinatorial treatment; none of the tested tumor cell lines exhibited a “high-grade resistance” pattern. Detailed investigation of the SCD prodrug system suggested that the cytotoxic effect of converted 5-FU is directed either against the cells or against the virus particles, depending on the balance between cell line-specific susceptibility to GLV-1h94-induced oncolysis and 5-FU sensitivity. The data provided by this work underline that cellular resistance against VACV-based virotherapy can be overcome by virus-encoded prodrug systems. Phase I/II clinical trials are recommended to further elucidate the enormous potential of this combination therapy.https://www.mdpi.com/1422-0067/21/20/7618oncolytic virotherapyvirotherapy resistancevaccinia virusNCI-60 tumor cell panelsuper cytosine deaminase prodrug systemchemovirotherapy |
| spellingShingle | Susanne Berchtold Julia Beil Christian Raff Irina Smirnow Martina Schell Janina D’Alvise Silvia Gross Ulrich M. Lauer Assessing and Overcoming Resistance Phenomena against a Genetically Modified Vaccinia Virus in Selected Cancer Cell Lines International Journal of Molecular Sciences oncolytic virotherapy virotherapy resistance vaccinia virus NCI-60 tumor cell panel super cytosine deaminase prodrug system chemovirotherapy |
| title | Assessing and Overcoming Resistance Phenomena against a Genetically Modified Vaccinia Virus in Selected Cancer Cell Lines |
| title_full | Assessing and Overcoming Resistance Phenomena against a Genetically Modified Vaccinia Virus in Selected Cancer Cell Lines |
| title_fullStr | Assessing and Overcoming Resistance Phenomena against a Genetically Modified Vaccinia Virus in Selected Cancer Cell Lines |
| title_full_unstemmed | Assessing and Overcoming Resistance Phenomena against a Genetically Modified Vaccinia Virus in Selected Cancer Cell Lines |
| title_short | Assessing and Overcoming Resistance Phenomena against a Genetically Modified Vaccinia Virus in Selected Cancer Cell Lines |
| title_sort | assessing and overcoming resistance phenomena against a genetically modified vaccinia virus in selected cancer cell lines |
| topic | oncolytic virotherapy virotherapy resistance vaccinia virus NCI-60 tumor cell panel super cytosine deaminase prodrug system chemovirotherapy |
| url | https://www.mdpi.com/1422-0067/21/20/7618 |
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