TY - JOUR
T1 - Optimising measles virus-guided radiovirotherapy with external beam radiotherapy and specific checkpoint kinase 1 inhibition
AU - Touchefeu, Yann
AU - Khan, Aadil A.
AU - Borst, Gerben
AU - Zaidi, Shane H.
AU - McLaughlin, Martin
AU - Roulstone, Victoria
AU - Mansfield, David
AU - Kyula, Joan
AU - Pencavel, Tim
AU - Karapanagiotou, Eleni M.
AU - Clayton, Jamie
AU - Federspiel, Mark J.
AU - Russell, Steve J.
AU - Garrett, Michelle
AU - Collins, Ian
AU - Harrington, Kevin J.
N1 - Funding Information:
Y. Touchefeu has received a doctoral research grant from the Institut National du Cancer and a research grant from the Société Nationale Française de Gastro-Entérologie (Robert Tournut grant). Part of this work was undertaken in The Royal Marsden NHS Foundation Trust who received a proportion of its funding from the NHS Executive; the views expressed in this publication are those of the authors and not necessarily those of the NHS Executive. This work was supported by The Institute of Cancer Research, and Cancer Research UK Section of Radiotherapy [CRUK] grant number C46/A10588 and the Head and Neck Unit Cancer Research UK CTRC Programme Grant ( A13407 ). We acknowledge NHS funding to the NIHR Biomedical Research Centre. We also acknowledge support from the Institut National de la Santé et de la Recherche Médicale (INSERM) .
Funding Information:
We would like to acknowledge the outstanding work of the entire team of the Mayo Clinic Viral Vector Production Laboratory and thank the Mayo Foundation, Mayo Clinic Comprehensive Cancer Center ( CA15083 ), Al and Mary Agnes McQuinn and Richard M. Schulze Family Foundation for funding support.
Copyright:
Copyright 2013 Elsevier B.V., All rights reserved.
PY - 2013/7
Y1 - 2013/7
N2 - Background and purpose We previously reported a therapeutic strategy comprising replication-defective NIS-expressing adenovirus combined with radioiodide, external beam radiotherapy (EBRT) and DNA repair inhibition. We have now evaluated NIS-expressing oncolytic measles virus (MV-NIS) combined with NIS-guided radioiodide, EBRT and specific checkpoint kinase 1 (Chk1) inhibition in head and neck and colorectal models. Materials and methods Anti-proliferative/cytotoxic effects of individual agents and their combinations were measured by MTS, clonogenic and Western analysis. Viral gene expression was measured by radioisotope uptake and replication by one-step growth curves. Potential synergistic interactions were tested in vitro by Bliss independence analysis and in in vivo therapeutic studies. Results EBRT and MV-NIS were synergistic in vitro. Furthermore, EBRT increased NIS expression in infected cells. SAR-020106 was synergistic with EBRT, but also with MV-NIS in HN5 cells. MV-NIS mediated 131I-induced cytotoxicity in HN5 and HCT116 cells and, in the latter, this was enhanced by SAR-020106. In vivo studies confirmed that MV-NIS, EBRT and Chk1 inhibition were effective in HCT116 xenografts. The quadruplet regimen of MV-NIS, virally-directed 131I, EBRT and SAR-020106 had significant anti-tumour activity in HCT116 xenografts. Conclusion This study strongly supports translational and clinical research on MV-NIS combined with radiation therapy and radiosensitising agents.
AB - Background and purpose We previously reported a therapeutic strategy comprising replication-defective NIS-expressing adenovirus combined with radioiodide, external beam radiotherapy (EBRT) and DNA repair inhibition. We have now evaluated NIS-expressing oncolytic measles virus (MV-NIS) combined with NIS-guided radioiodide, EBRT and specific checkpoint kinase 1 (Chk1) inhibition in head and neck and colorectal models. Materials and methods Anti-proliferative/cytotoxic effects of individual agents and their combinations were measured by MTS, clonogenic and Western analysis. Viral gene expression was measured by radioisotope uptake and replication by one-step growth curves. Potential synergistic interactions were tested in vitro by Bliss independence analysis and in in vivo therapeutic studies. Results EBRT and MV-NIS were synergistic in vitro. Furthermore, EBRT increased NIS expression in infected cells. SAR-020106 was synergistic with EBRT, but also with MV-NIS in HN5 cells. MV-NIS mediated 131I-induced cytotoxicity in HN5 and HCT116 cells and, in the latter, this was enhanced by SAR-020106. In vivo studies confirmed that MV-NIS, EBRT and Chk1 inhibition were effective in HCT116 xenografts. The quadruplet regimen of MV-NIS, virally-directed 131I, EBRT and SAR-020106 had significant anti-tumour activity in HCT116 xenografts. Conclusion This study strongly supports translational and clinical research on MV-NIS combined with radiation therapy and radiosensitising agents.
KW - External beam radiation therapy
KW - Oncolytic measles virus
KW - Radiation-sensitizing agents
KW - Radiovirotherapy
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U2 - 10.1016/j.radonc.2013.05.036
DO - 10.1016/j.radonc.2013.05.036
M3 - Article
C2 - 23849174
AN - SCOPUS:84883161214
SN - 0167-8140
VL - 108
SP - 24
EP - 31
JO - Radiotherapy and Oncology
JF - Radiotherapy and Oncology
IS - 1
ER -