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dc.contributor.authorWilkinson, MJ
dc.contributor.authorSmith, HG
dc.contributor.authorMcEntee, G
dc.contributor.authorKyula-Currie, J
dc.contributor.authorPencavel, TD
dc.contributor.authorMansfield, DC
dc.contributor.authorKhan, AA
dc.contributor.authorRoulstone, V
dc.contributor.authorHayes, AJ
dc.contributor.authorHarrington, KJ
dc.date.accessioned2017-01-18T15:14:07Z
dc.date.issued2016-12-06
dc.identifier.citationOncotarget, 2016, 7 (49), pp. 81208 - 81222
dc.identifier.issn1949-2553
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/390
dc.identifier.eissn1949-2553
dc.identifier.doi10.18632/oncotarget.12820
dc.description.abstractAdvanced extremity melanoma and sarcoma present a significant therapeutic challenge, requiring multimodality therapy to treat or even palliate disease. These aggressive tumours are relatively chemo-resistant, therefore new treatment approaches are urgently required. We have previously reported on the efficacy of oncolytic virotherapy (OV) delivered by isolated limb perfusion. In this report, we have improved therapeutic outcomes by combining OV with radiotherapy. In vitro, the combination of oncolytic vaccinia virus (GLV-1h68) and radiotherapy demonstrated synergistic cytotoxicity. This effect was not due to increased viral replication, but mediated through induction of intrinsic apoptosis. GLV-1h68 therapy downregulated the anti-apoptotic BCL-2 proteins (MCL-1 and BCL-XL) and the downstream inhibitors of apoptosis, resulting in cleavage of effector caspases 3 and 7. In an in vivo ILP model, the combination of OV and radiotherapy significantly delayed tumour growth and prolonged survival compared to single agent therapy. These data suggest that the virally-mediated down-regulation of anti-apoptotic proteins may increase the sensitivity of tumour cells to the cytotoxic effects of ionizing radiation. Oncolytic virotherapy represents an exciting candidate for clinical development when delivered by ILP. Its ability to overcome anti-apoptotic signals within tumour cells points the way to further development in combination with conventional anti-cancer therapies.
dc.formatPrint
dc.format.extent81208 - 81222
dc.languageeng
dc.language.isoeng
dc.publisherIMPACT JOURNALS LLC
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.subjectCell Line, Tumor
dc.subjectAnimals
dc.subjectRats, Inbred BN
dc.subjectHumans
dc.subjectVaccinia virus
dc.subjectFibrosarcoma
dc.subjectRadiotherapy, Adjuvant
dc.subjectDose-Response Relationship, Radiation
dc.subjectSignal Transduction
dc.subjectApoptosis
dc.subjectGene Expression Regulation, Neoplastic
dc.subjectTime Factors
dc.subjectMale
dc.subjectOncolytic Virotherapy
dc.subjectOncolytic Viruses
dc.subjectApoptosis Regulatory Proteins
dc.subjectbcl-X Protein
dc.subjectCaspase 3
dc.subjectCaspase 7
dc.subjectHost-Pathogen Interactions
dc.subjectMyeloid Cell Leukemia Sequence 1 Protein
dc.titleOncolytic vaccinia virus combined with radiotherapy induces apoptotic cell death in sarcoma cells by down-regulating the inhibitors of apoptosis.
dc.typeJournal Article
dcterms.dateAccepted2016-10-11
rioxxterms.versionofrecord10.18632/oncotarget.12820
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2016-12
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfOncotarget
pubs.issue49
pubs.notesNo embargo
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology/Targeted Therapy
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging/Sarcoma and Melanoma Surgery
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging/Targeted Therapy
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Biology/Targeted Therapy
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging/Sarcoma and Melanoma Surgery
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging/Targeted Therapy
pubs.publication-statusPublished
pubs.volume7
pubs.embargo.termsNo embargo
icr.researchteamSarcoma and Melanoma Surgery
icr.researchteamTargeted Therapy
dc.contributor.icrauthorMansfield, David
dc.contributor.icrauthorRoulstone, Victoria
dc.contributor.icrauthorHarrington, Kevin


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