Luo Xian, Slater James M, Gridley Daila S
Department of Biochemistry and Microbiology, Loma Linda University and Medical Center, Loma Linda, CA 92354, USA.
Int J Radiat Oncol Biol Phys. 2005 Oct 1;63(2):553-64. doi: 10.1016/j.ijrobp.2005.01.038.
Endostatin is a potent antiangiogenesis protein with little or no toxicity that has potential to enhance radiotherapy. The major goal of this study was to evaluate the combination of radiation and endostatin gene therapy in a preclinical lung cancer model.
Plasmid pXLG-mEndo, constructed in our laboratory, includes the mouse endostatin gene cloned into the pWS4 vector. The kinetics of endostatin expression and efficacy of the pXLG-mEndo and radiation ((60)Co gamma-rays) combination was evaluated in the C57BL/6 mouse-Lewis lung carcinoma (LLC) model. The LLC cells were implanted s.c. and pXLG-mEndo was injected intratumorally 12-14 days later without any transfection agent; a dose of 10 Gy radiation was applied approximately 16 h thereafter. Some groups received each modality twice. Endostatin, vascular endothelial growth factor (VEGF), and transforming growth factor-beta1 (TGF-beta1) were quantified in plasma and tumors, and tumor vasculature was examined.
Endostatin expression within LLC tumors peaked on Day 7 after pXLG-mEndo injection. Addition of radiation to pXLG-mEndo significantly enhanced the level of tumor endostatin compared with plasmid alone (p < 0.05). Tumor growth was significantly delayed in mice receiving pXLG-mEndo plus radiation compared with no treatment (p < 0.005), radiation (p < 0.05), and control plasmid (p < 0.05). The number of LLC tumor vessels was reduced after combined treatment (p < 0.05), and significant treatment-related changes were observed in both VEGF and TGF-beta1.
The data demonstrate that delivery of endostatin by pXLG-mEndo as an adjuvant to radiation can significantly enhance the antitumor efficacy of radiotherapy in the LLC mouse tumor model and support further investigation of this unique combination therapy.
内皮抑素是一种具有强大抗血管生成作用且几乎无毒性的蛋白质，具有增强放射治疗效果的潜力。本研究的主要目的是在临床前肺癌模型中评估放射治疗与内皮抑素基因治疗的联合应用。
我们实验室构建的质粒pXLG-mEndo，包含克隆到pWS4载体中的小鼠内皮抑素基因。在C57BL/6小鼠-刘易斯肺癌（LLC）模型中评估内皮抑素的表达动力学以及pXLG-mEndo与放射治疗（（60）Coγ射线）联合应用的效果。将LLC细胞皮下接种，12 - 14天后在不使用任何转染剂的情况下将pXLG-mEndo瘤内注射；此后约16小时给予10 Gy的放射剂量。部分组每种治疗方式给予两次。对血浆和肿瘤中的内皮抑素、血管内皮生长因子（VEGF）和转化生长因子-β1（TGF-β1）进行定量，并检查肿瘤血管系统。
pXLG-mEndo注射后第7天，LLC肿瘤内的内皮抑素表达达到峰值。与单独使用质粒相比，pXLG-mEndo联合放射治疗显著提高了肿瘤内皮抑素水平（p < 0.05）。与未治疗组（p < 0.005）、放射治疗组（p < 0.05）和对照质粒组（p < 0.05）相比，接受pXLG-mEndo联合放射治疗的小鼠肿瘤生长明显延迟。联合治疗后LLC肿瘤血管数量减少（p < 0.05），并且在VEGF和TGF-β1中均观察到与治疗相关的显著变化。
数据表明，通过pXLG-mEndo递送内皮抑素作为放射治疗的辅助手段，可显著提高LLC小鼠肿瘤模型中放射治疗的抗肿瘤效果，并支持对这种独特联合治疗进行进一步研究。
