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dc.contributor.authorKhan, AAen_US
dc.contributor.authorPaget, JTen_US
dc.contributor.authorMcLaughlin, Men_US
dc.contributor.authorKyula, JNen_US
dc.contributor.authorWilkinson, MJen_US
dc.contributor.authorPencavel, Ten_US
dc.contributor.authorMansfield, Den_US
dc.contributor.authorRoulstone, Ven_US
dc.contributor.authorSeth, Ren_US
dc.contributor.authorHalle, Men_US
dc.contributor.authorSomaiah, Nen_US
dc.contributor.authorBoult, JKRen_US
dc.contributor.authorRobinson, SPen_US
dc.contributor.authorPandha, HSen_US
dc.contributor.authorVile, RGen_US
dc.contributor.authorMelcher, AAen_US
dc.contributor.authorHarris, PAen_US
dc.contributor.authorHarrington, KJen_US
dc.coverage.spatialUnited Statesen_US
dc.date.accessioned2018-04-23T15:11:44Z
dc.date.issued2018-01-24en_US
dc.identifierhttps://www.ncbi.nlm.nih.gov/pubmed/29367346en_US
dc.identifier10/425/eaar2041en_US
dc.identifier.citationSci Transl Med, 2018, 10 (425)en_US
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/1652
dc.identifier.eissn1946-6242en_US
dc.identifier.doi10.1126/scitranslmed.aar2041en_US
dc.description.abstractImprovements in cancer survival mean that long-term toxicities, which contribute to the morbidity of cancer survivorship, are being increasingly recognized. Late adverse effects (LAEs) in normal tissues after radiotherapy (RT) are characterized by vascular dysfunction and fibrosis causing volume loss and tissue contracture, for example, in the free flaps used for immediate breast reconstruction after mastectomy. We evaluated the efficacy of lentivirally delivered superoxide dismutase 2 (SOD2) overexpression and connective tissue growth factor (CTGF) knockdown by short hairpin RNA in reducing the severity of LAEs in an animal model of free flap LAEs. Vectors were delivered by intra-arterial injection, ex vivo, to target the vascular compartment. LVSOD2 and LVshCTGF monotherapy before irradiation resulted in preservation of flap volume or reduction in skin contracture, respectively. Flaps transduced with combination therapy experienced improvements in both volume loss and skin contracture. Both therapies reduced the fibrotic burden after irradiation. LAEs were associated with impaired vascular perfusion, loss of endothelial permeability, and stromal hypoxia, which were all reversed in the treatment model. Using a tumor recurrence model, we showed that SOD2 overexpression in normal tissues did not compromise the efficacy of RT against tumor cells but appeared to enhance it. LVSOD2 and LVshCTGF combination therapy by targeted, intravascular delivery reduced LAE severities in normal tissues without compromising the efficacy of RT and warrants translational evaluation as a free flap-targeted gene therapy.en_US
dc.languageengen_US
dc.language.isoengen_US
dc.rights.urihttp://www.rioxx.net/licenses/under-embargo-all-rights-reserveden_US
dc.titleGenetically modified lentiviruses that preserve microvascular function protect against late radiation damage in normal tissues.en_US
dc.typeJournal Article
dcterms.dateAccepted2017-11-08en_US
rioxxterms.versionofrecord10.1126/scitranslmed.aar2041en_US
rioxxterms.licenseref.startdate2018-01-24en_US
rioxxterms.typeJournal Article/Reviewen_US
dc.relation.isPartOfSci Transl Meden_US
pubs.issue425en_US
pubs.notesNo embargoen_US
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/Magnetic Resonance
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging/Targeted Therapy
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging/Translational Immunotherapy
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging/Translational Immunotherapy/Translational Immunotherapy (TL)
pubs.publication-statusPublisheden_US
pubs.volume10en_US
pubs.embargo.termsNo embargoen_US
icr.researchteamMagnetic Resonanceen_US
icr.researchteamTargeted Therapyen_US
icr.researchteamTranslational Immunotherapyen_US
dc.contributor.icrauthorHarrington, Kevinen_US
dc.contributor.icrauthorRobinson, Simonen_US
dc.contributor.icrauthorBoult, Jessicaen_US
dc.contributor.icrauthorMansfield, Daviden_US
dc.contributor.icrauthorSomaiah, Navitaen_US
dc.contributor.icrauthorKhan, Aadilen_US
dc.contributor.icrauthorMelcher, Alanen_US


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