Liu Lin Lin, Smith Myles J, Sun Bao Sheng, Wang Guan Jun, Redmond H Paul, Wang Jiang Huai
Department of Academic Surgery, University College Cork (UCC)/National University of Ireland (NUI), Cork University Hospital, Cork, Ireland.
Ann Surg Oncol. 2009 May;16(5):1403-11. doi: 10.1245/s10434-009-0343-6. Epub 2009 Mar 5.
Gene-radiotherapy, a combination of gene therapy and radiotherapy, is a new paradigm for cancer treatment, with the potential to simultaneously improve local and systemic breast cancer control. The aim of this study was to evaluate antitumor effect of interferon (IFN)-gamma-endostatin-based gene-radiotherapy in a murine metastatic breast tumor model, and to elucidate possible mechanisms involved.
Murine mammary adenocarcinoma 4T1 cells transfected with pEgr-IFN-gamma and pEgr-endostatin plasmids were irradiated (2-20 Gy). IFN-gamma and endostatin levels in the culture supernatants were measured. In vivo female BALB/c mice were inoculated with 1 x 10(5) 4T1 cells by mammary fat pad injection and divided into control, empty vector, gene therapy (pEgr-IFN-gamma and pEgr-endostatin), radiotherapy, and combined gene-radiotherapy groups. Tumor growth, tumor/body weight ratio, lung metastases, and survival of the tumor-bearing mice were observed. Splenic cytotoxic T-lymphocyte (CTL) and natural killer (NK) cell activity and intratumor microvessel density were also assessed.
Irradiation significantly enhanced IFN-gamma and endostatin secretion from the transfected 4T1 cells. In vivo mice that received combined gene-radiotherapy showed maximal attenuation in tumor growth rate and lung metastases with increased survival compared with mice that received gene therapy or radiotherapy alone. This was associated with significantly enhanced CTL and NK cell activity and reduced intratumor microvessel density.
These results demonstrate that IFN-gamma-endostatin-based gene-radiotherapy provide a potent antitumor effect in a murine metastatic breast tumor model, which may relate to IFN-gamma-stimulated CTL and NK cell activation, and endostatin-induced antiangiogenic activity. Thus, gene-radiotherapy may represent a useful addition to neoadjuvant management of locally advanced breast cancer.
基因放疗是基因治疗与放疗的结合，是癌症治疗的一种新范式，具有同时改善局部和全身乳腺癌控制的潜力。本研究的目的是评估基于干扰素（IFN）-γ-内皮抑素的基因放疗在小鼠转移性乳腺肿瘤模型中的抗肿瘤作用，并阐明其可能的作用机制。
用pEgr-IFN-γ和pEgr-内皮抑素质粒转染的小鼠乳腺腺癌4T1细胞接受照射（2-20 Gy）。测量培养上清液中IFN-γ和内皮抑素水平。在体内，通过乳腺脂肪垫注射将1×10(5)个4T1细胞接种到雌性BALB/c小鼠体内，并将其分为对照组、空载体组、基因治疗组（pEgr-IFN-γ和pEgr-内皮抑素）、放疗组和联合基因放疗组。观察荷瘤小鼠的肿瘤生长、肿瘤/体重比、肺转移和生存情况。还评估了脾脏细胞毒性T淋巴细胞（CTL）和自然杀伤（NK）细胞活性以及肿瘤内微血管密度。
照射显著增强了转染的4T1细胞中IFN-γ和内皮抑素的分泌。在体内，与单独接受基因治疗或放疗的小鼠相比，接受联合基因放疗的小鼠肿瘤生长速率和肺转移的衰减最大，生存期延长。这与CTL和NK细胞活性显著增强以及肿瘤内微血管密度降低有关。
这些结果表明，基于IFN-γ-内皮抑素的基因放疗在小鼠转移性乳腺肿瘤模型中具有强大的抗肿瘤作用，这可能与IFN-γ刺激的CTL和NK细胞活化以及内皮抑素诱导的抗血管生成活性有关。因此，基因放疗可能是局部晚期乳腺癌新辅助治疗的有益补充。
