Loeffler Markus, Le'Negrate Gaelle, Krajewska Maryla, Reed John C
Burnham Institute for Medical Research, La Jolla, CA 92037, USA.
Proc Natl Acad Sci U S A. 2007 Jul 31;104(31):12879-83. doi: 10.1073/pnas.0701959104. Epub 2007 Jul 24.
Intravenously administered bacteria reportedly accumulate in tumors. Furthermore, systemic administration of attenuated Salmonella typhimurium has little or no significant side-effects in humans. Consequently, we engineered such bacteria to improve their oncolytic activity by stably inserting a gene encoding LIGHT, a cytokine known to promote tumor rejection. Unlike control bacteria, attenuated S. typhimurium expressing LIGHT inhibited growth of primary tumors, as well as the dissemination of pulmonary metastases, in various mouse tumor models employing murine carcinoma cell lines in immunocompetent mice. Antitumor activity was achieved without significant toxicity and was associated with infiltration of inflammatory cells and dependent on the LIGHT receptors, herpes virus entry mediator (HVEM), and lymphotoxin-beta receptor (LTbetaR). These findings provide evidence that nonvirulent bacteria can be exploited as targeting vehicles for local generation of therapeutic proteins in tumors.
据报道，静脉注射的细菌会在肿瘤中积聚。此外，减毒鼠伤寒沙门氏菌的全身给药在人体中几乎没有或没有明显的副作用。因此，我们对这种细菌进行了改造，通过稳定插入一个编码LIGHT的基因来提高其溶瘤活性，LIGHT是一种已知可促进肿瘤排斥的细胞因子。与对照细菌不同，表达LIGHT的减毒鼠伤寒沙门氏菌在使用免疫活性小鼠的鼠癌细胞系的各种小鼠肿瘤模型中，抑制了原发性肿瘤的生长以及肺转移的扩散。在没有明显毒性的情况下实现了抗肿瘤活性，并且与炎性细胞浸润相关，且依赖于LIGHT受体、疱疹病毒进入介质（HVEM）和淋巴毒素-β受体（LTβR）。这些发现提供了证据，表明无毒细菌可被用作在肿瘤中局部产生治疗性蛋白质的靶向载体。
