The State Key Laboratory of Pharmaceutical Biotechnology and School of Stomatology, Affiliated Stomatological Hospital, Nanjing University, Nanjing, China.
Cancer Sci. 2012 Feb;103(2):325-33. doi: 10.1111/j.1349-7006.2011.02147.x. Epub 2011 Dec 15.
Attenuated Salmonella typhimurium (S. typhimurium) strains can selectively grow and express exogenous genes in tumors for targeted therapy. We engineered S. typhimurium strain VNP20009 to secrete tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) under the control of a hypoxia-induced nirB promoter and examined the efficacy of Salmonella-mediated targeted expression of TRAIL in mice bearing melanoma tumor and in TRAIL-resistant RM-1 tumor. We found that VNP preferentially accumulated in tumor tissues and the nirB promoter effectively drove targeted expression of TRAIL. Compared with recombinant TRAIL protein and VNP20009 combination therapy, VNP20009 expressing TRAIL significantly suppressed melanoma growth but failed to suppress RM-1 tumor growth. Furthermore, we confirmed that VNP20009 expressing TRAIL yielded its antitumor effect by inducing melanoma apoptosis. Our findings indicate that Salmonella-mediated tumor-targeted therapy with TRAIL could reduce tumor growth and extend host survival.
减毒鼠伤寒沙门氏菌（S. typhimurium）株可以在肿瘤中选择性地生长和表达外源基因，用于靶向治疗。我们设计了鼠伤寒沙门氏菌菌株 VNP20009，使其在缺氧诱导的nirB 启动子的控制下分泌肿瘤坏死因子相关凋亡诱导配体（TRAIL），并在携带黑色素瘤肿瘤的小鼠和 TRAIL 耐药的 RM-1 肿瘤中研究了沙门氏菌介导的 TRAIL 靶向表达的疗效。我们发现 VNP 优先积聚在肿瘤组织中，nirB 启动子有效地驱动 TRAIL 的靶向表达。与重组 TRAIL 蛋白和 VNP20009 联合治疗相比，表达 TRAIL 的 VNP20009 显著抑制了黑色素瘤的生长，但未能抑制 RM-1 肿瘤的生长。此外，我们证实表达 TRAIL 的 VNP20009 通过诱导黑色素瘤细胞凋亡发挥其抗肿瘤作用。我们的研究结果表明，沙门氏菌介导的 TRAIL 肿瘤靶向治疗可以减少肿瘤生长并延长宿主的生存时间。
