Journal
SCIENCE TRANSLATIONAL MEDICINE
Volume 10, Issue 425, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.aar2041
Keywords
-
Categories
Funding
- Wellcome Trust [WT098937MF, 200175/Z/15]
- Royal College of Surgeons of England
- British Association of Plastic, Reconstructive and Aesthetic Surgeons
- Masons Medical Research Foundation
- Institute of Cancer Research (ICR)/Royal Marsden Hospital National Institute for Health Research Biomedical Research Centre
- Rosetrees Trust
- Oracle Cancer Trust
- Anthony Long Trust
- Institute of Cancer Research's Cancer Research UK
- Engineering and Physical Sciences Research Council Cancer Imaging Centre [C1060/A10334]
- Cancer Research Cancer Imaging Centre [C1090/A16464]
- Medical Research Council
- Cancer Research Funds of Radiumhemmet
- Stockholm County Council
- Swedish Society of Medicine
- Department of Health (England)
- Academy of Medical Sciences (AMS) [SGL017\\1026] Funding Source: researchfish
- Cancer Research UK [21855, 16464] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0515-10101, CL-2014-22-003] Funding Source: researchfish
Ask authors/readers for more resources
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available