dc.contributor.author | Khan, AA | |
dc.contributor.author | Paget, JT | |
dc.contributor.author | McLaughlin, M | |
dc.contributor.author | Kyula, JN | |
dc.contributor.author | Wilkinson, MJ | |
dc.contributor.author | Pencavel, T | |
dc.contributor.author | Mansfield, D | |
dc.contributor.author | Roulstone, V | |
dc.contributor.author | Seth, R | |
dc.contributor.author | Halle, M | |
dc.contributor.author | Somaiah, N | |
dc.contributor.author | Boult, JKR | |
dc.contributor.author | Robinson, SP | |
dc.contributor.author | Pandha, HS | |
dc.contributor.author | Vile, RG | |
dc.contributor.author | Melcher, AA | |
dc.contributor.author | Harris, PA | |
dc.contributor.author | Harrington, KJ | |
dc.date.accessioned | 2018-04-23T15:11:44Z | |
dc.date.issued | 2018-01-24 | |
dc.identifier.citation | Science translational medicine, 2018, 10 (425) | |
dc.identifier.issn | 1946-6234 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/1652 | |
dc.identifier.eissn | 1946-6242 | |
dc.identifier.doi | 10.1126/scitranslmed.aar2041 | |
dc.description.abstract | Improvements 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. | |
dc.format | Print | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | AMER ASSOC ADVANCEMENT SCIENCE | |
dc.rights.uri | https://www.rioxx.net/licenses/under-embargo-all-rights-reserved | |
dc.subject | Surgical Flaps | |
dc.subject | Mitochondria | |
dc.subject | Endothelial Cells | |
dc.subject | Skin | |
dc.subject | Animals | |
dc.subject | Rats, Inbred F344 | |
dc.subject | Humans | |
dc.subject | Lentivirus | |
dc.subject | Radiation Injuries | |
dc.subject | Fibrosis | |
dc.subject | Superoxide Dismutase | |
dc.subject | Magnetic Resonance Imaging | |
dc.subject | Reproducibility of Results | |
dc.subject | Cell Death | |
dc.subject | Phenotype | |
dc.subject | Transgenes | |
dc.subject | X-Rays | |
dc.subject | Male | |
dc.subject | Connective Tissue Growth Factor | |
dc.subject | Microvessels | |
dc.subject | HEK293 Cells | |
dc.subject | Genetic Therapy | |
dc.title | Genetically modified lentiviruses that preserve microvascular function protect against late radiation damage in normal tissues. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2017-11-08 | |
rioxxterms.versionofrecord | 10.1126/scitranslmed.aar2041 | |
rioxxterms.licenseref.uri | https://www.rioxx.net/licenses/under-embargo-all-rights-reserved | |
rioxxterms.licenseref.startdate | 2018-01 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Science translational medicine | |
pubs.issue | 425 | |
pubs.notes | No 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/Pre-Clinical MRI | |
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 Breast Radiobiology | |
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.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/Pre-Clinical MRI | |
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 Breast Radiobiology | |
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-status | Published | |
pubs.volume | 10 | |
pubs.embargo.terms | No embargo | |
icr.researchteam | Pre-Clinical MRI | |
icr.researchteam | Targeted Therapy | |
icr.researchteam | Translational Breast Radiobiology | |
icr.researchteam | Translational Immunotherapy | |
dc.contributor.icrauthor | McLaughlin, Martin | |
dc.contributor.icrauthor | Mansfield, David | |
dc.contributor.icrauthor | Roulstone, Victoria | |
dc.contributor.icrauthor | Somaiah, Navita | |
dc.contributor.icrauthor | Boult, Jessica | |
dc.contributor.icrauthor | Robinson, Simon | |
dc.contributor.icrauthor | Melcher, Alan | |
dc.contributor.icrauthor | Harrington, Kevin | |