Targeted Therapy Team, Division of Radiotherapy and Imaging, The Institute of Cancer Research, London SW3 6JB, UK.
Department of Plastic Surgery, The Royal Marsden Hospital, London SW3 6JJ, UK.
Sci Transl Med. 2018 Jan 24;10(425). doi: 10.1126/scitranslmed.aar2041.
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.
癌症存活率的提高意味着长期毒性作用（导致癌症生存者发病率上升的原因）正日益受到关注。放射治疗（RT）后正常组织的晚期不良反应（LAE）的特征是血管功能障碍和纤维化，导致体积损失和组织挛缩，例如在乳房切除术后立即进行乳房重建中使用的游离皮瓣。我们评估了通过慢病毒传递超氧化物歧化酶 2（SOD2）过表达和短发夹 RNA 下调结缔组织生长因子（CTGF）在减少游离皮瓣 LAE 动物模型中 LAE 严重程度的疗效。通过动脉内注射将载体递送至血管腔室进行离体转导。在照射前进行 LVSOD2 和 LVshCTGF 单药治疗分别导致皮瓣体积保持或皮肤挛缩减少。联合治疗转导的皮瓣在体积损失和皮肤挛缩方面均有所改善。两种治疗方法均减少了照射后的纤维化负担。LAE 与血管灌注受损、内皮通透性丧失和基质缺氧有关，在治疗模型中这些均得到了逆转。使用肿瘤复发模型，我们表明正常组织中的 SOD2 过表达不会影响 RT 对肿瘤细胞的疗效，但似乎增强了疗效。通过靶向血管内递送的 LVSOD2 和 LVshCTGF 联合治疗可降低正常组织中的 LAE 严重程度，而不影响 RT 的疗效，值得作为一种游离皮瓣靶向基因治疗进行转化评估。
