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Synergistic cytotoxicity of oncolytic reovirus in combination with cisplatin–paclitaxel doublet chemotherapy

Gene Therapy volume 20, pages 521–528 (2013)Cite this article

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Abstract

Oncolytic reovirus is currently under active investigation in a range of tumour types. Early phase studies have shown that this agent has modest monotherapy efficacy and its future development is likely to focus on combination regimens with cytotoxic chemotherapy. Indeed, phase I/II clinical trials have confirmed that reovirus can be safely combined with cytotoxic drugs, including a platin–taxane doublet regimen, which is currently being tested in a phase III clinical trial in patients with relapsed/metastatic head and neck cancer. Therefore, we have tested this triple (reovirus, cisplatin, paclitaxel) combination therapy in a panel of four head and neck cancer cell lines. Using the combination index (CI) method, the triple therapy demonstrated synergistic cytotoxicity in vitro in both malignant and non-malignant cell lines. In head and neck cancer cell lines, this was associated with enhanced caspase 3 and 7 cleavage, but no increase in viral replication. In vitro analyses confirmed colocalisation of markers of reovirus infection and caspase 3. Triple therapy was significantly more effective than reovirus or cisplatin–paclitaxel in athymic nude mice. These data suggest that the combination of reovirus plus platin–taxane doublet chemotherapy has significant activity in head and neck cancer and underpin the current phase III study in this indication.

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Acknowledgements

We thank Oncolytics Biotech for providing the reovirus.

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Authors and Affiliations

  1. Division of Cell Biology, Targeted Therapy Laboratory, Section of Cell and Molecular Biology, Chester Beatty Laboratories, The Institute of Cancer Research, London, UK

    V Roulstone, K Twigger, S Zaidi, T Pencavel, J N Kyula, C White, M McLaughlin, R Seth, E M Karapanagiotou, D Mansfield & K J Harrington

  2. Oncolytics Biotech Inc., Calgary, Alberta, Canada

    M Coffey

  3. Ohio State University, Columbus, OH, USA

    G Nuovo

  4. Leeds Institute of Molecular Medicine, Leeds, UK

    R G Vile & A A Melcher

  5. Molecular Medicine Program, Mayo Clinic, Rochester, MN

    R G Vile

  6. USA,

    R G Vile

  7. Postgraduate Medical School, The University of Surrey, Guildford, UK

    H S Pandha

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  1. V Roulstone
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  2. K Twigger
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  3. S Zaidi
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  8. R Seth
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  9. E M Karapanagiotou
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  15. A A Melcher
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  16. K J Harrington
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Corresponding author

Correspondence to K J Harrington.

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Competing interests

Matt Coffey is a shareholder and employee of Oncolytics Biotech Inc., and Gerard Nuovo, Richard Vile, Alan Melcher and Kevin Harrington received funding from Oncolytics Biotech Inc. in support of the laboratory research.

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Roulstone, V., Twigger, K., Zaidi, S. et al. Synergistic cytotoxicity of oncolytic reovirus in combination with cisplatin–paclitaxel doublet chemotherapy. Gene Ther 20, 521–528 (2013). https://doi.org/10.1038/gt.2012.68

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