PURPOSE: To test combination treatment schedules of reovirus and cisplatin chemotherapy in human and murine melanoma cell lines and murine models of melanoma and to investigate the possible mechanisms of synergistic antitumor effects. EXPERIMENTAL DESIGN: The effects of reovirus +/- chemotherapy on in vitro cytotoxicity and viral replication were assessed using 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assay and plaque assay. Interactions between agents were assessed by combination index analysis. Mode of cell death was assessed by Annexin V/propidium iodide fluorescence-activated cell sorting-based assays; gene expression profiling of single versus combination treatments was completed using the Agilent microarray system. Single agent and combination therapy effects were tested in vivo in two immunocompetent models of murine melanoma. RESULTS: Variable degrees of synergistic cytotoxicity between live reovirus and several chemotherapy agents were observed in B16.F10 mouse melanoma cells, most significantly with cisplatin (combination index of 0.42 +/- 0.03 at ED(50)). Combination of cisplatin and reovirus exposure led to increased late apoptotic/necrotic cell populations. Cisplatin almost completely abrogated the inflammatory cytokine gene up-regulation induced by reovirus. Combination therapy led to significantly delayed tumor growth and improved survival in vivo (P < 0.0001 and P = 0.0003, respectively). Cisplatin had no effect on the humoral response to reovirus in mice. However, cisplatin treatment suppressed the cytokine and chemokine response to reovirus in vitro and in vivo. CONCLUSION: The combination of reovirus and several chemotherapeutic agents synergistically enhanced cytotoxicity in human and murine melanoma cell lines in vitro and murine tumors in vivo. The data support the current reovirus/chemotherapy combination phase I clinical studies currently ongoing in the clinic.
PURPOSE: To test combination treatment schedules of reovirus and cisplatin chemotherapy in human and murinemelanoma cell lines and murine models of melanoma and to investigate the possible mechanisms of synergistic antitumor effects. EXPERIMENTAL DESIGN: The effects of reovirus +/- chemotherapy on in vitro cytotoxicity and viral replication were assessed using 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assay and plaque assay. Interactions between agents were assessed by combination index analysis. Mode of cell death was assessed by Annexin V/propidium iodide fluorescence-activated cell sorting-based assays; gene expression profiling of single versus combination treatments was completed using the Agilent microarray system. Single agent and combination therapy effects were tested in vivo in two immunocompetent models of murinemelanoma. RESULTS: Variable degrees of synergistic cytotoxicity between live reovirus and several chemotherapy agents were observed in B16.F10 mousemelanoma cells, most significantly with cisplatin (combination index of 0.42 +/- 0.03 at ED(50)). Combination of cisplatin and reovirus exposure led to increased late apoptotic/necrotic cell populations. Cisplatin almost completely abrogated the inflammatory cytokine gene up-regulation induced by reovirus. Combination therapy led to significantly delayed tumor growth and improved survival in vivo (P < 0.0001 and P = 0.0003, respectively). Cisplatin had no effect on the humoral response to reovirus in mice. However, cisplatin treatment suppressed the cytokine and chemokine response to reovirus in vitro and in vivo. CONCLUSION: The combination of reovirus and several chemotherapeutic agents synergistically enhanced cytotoxicity in human and murinemelanoma cell lines in vitro and murinetumors in vivo. The data support the current reovirus/chemotherapy combination phase I clinical studies currently ongoing in the clinic.
Authors: Charles Comins; James Spicer; Andrew Protheroe; Victoria Roulstone; Katie Twigger; Christine M White; Richard Vile; Alan Melcher; Matt C Coffey; Karl L Mettinger; Gerard Nuovo; David E Cohn; Mitch Phelps; Kevin J Harrington; Hardev S Pandha Journal: Clin Cancer Res Date: 2010-10-06 Impact factor: 12.531
Authors: Eleni M Karapanagiotou; Victoria Roulstone; Katie Twigger; Mercel Ball; Maryanne Tanay; Chris Nutting; Kate Newbold; Martin E Gore; James Larkin; Konstantinos N Syrigos; Matt Coffey; Brad Thompson; Karl Mettinger; Richard G Vile; Hardev S Pandha; Geoff D Hall; Alan A Melcher; John Chester; Kevin J Harrington Journal: Clin Cancer Res Date: 2012-02-07 Impact factor: 12.531
Authors: Christoforos Kosmidis; Konstantinos Sapalidis; Efstathios Kotidis; Nikolaos Mixalopoulos; Paul Zarogoulidis; Drosos Tsavlis; Sofia Baka; Yan-Gao Man; John Kanellos Journal: Ann Transl Med Date: 2016-05
Authors: Victoria Roulstone; Malin Pedersen; Joan Kyula; David Mansfield; Aadil A Khan; Grainne McEntee; Michelle Wilkinson; Eleni Karapanagiotou; Matt Coffey; Richard Marais; Adel Jebar; Fiona Errington-Mais; Alan Melcher; Richard Vile; Hardev Pandha; Martin McLaughlin; Kevin J Harrington Journal: Mol Ther Date: 2015-01-26 Impact factor: 11.454
Authors: Jason P Fernandes; Francisca Cristi; Heather E Eaton; Patricia Chen; Sarah Haeflinger; Isabelle Bernard; Mary M Hitt; Maya Shmulevitz Journal: J Virol Date: 2019-10-29 Impact factor: 5.103
Authors: Jay D Naik; Christopher J Twelves; Peter J Selby; Richard G Vile; John D Chester Journal: Clin Cancer Res Date: 2011-05-16 Impact factor: 12.531