Instititute of Genetics, School of Life Sciences, Fudan University, Shanghai, China.
Acta Pharmacol Sin. 2011 Mar;32(3):368-74. doi: 10.1038/aps.2010.224.
To examine whether attenuated Salmonella typhimurium (S typhimurium) could be used as an anti-cancer agent or a tumor-targeting vehicle for delivering shRNA-expressing pDNA into cancer cells in a mouse tumor model.
Mouse bladder transitional cancer cell line (BTT-T739) expressing GFP was used, in which the GFP expression level served as an indicator of RNA interference (RNAi). BTT-T739-GFP tumor-bearing mice (4-6 weeks) were treated with S typhimurium carrying plasmids encoding shRNA against gfp or scrambled shRNA. The mRNA and protein expression levels of GFP were assessed 5 d after the bacteria administration, and the antitumor effects of S typhimurium were evaluated.
In BTT-T739-GFP tumor-bearing mice, S typhimurium (1×10(9) cfu, po) preferentially accumulated within tumors for as long as 40 d, and formed a tumor-to-normal tissue ratio that exceeded 1000/1. S typhimurium carrying plasmids encoding shRNA against gfp inhibited the expression of GFP in tumor cells by 73.4%. Orally delivered S typhimurium significantly delayed tumor growth and prolonged the survival of tumor-bearing mice.
This study demonstrates that attenuated S typhimurium can be used for both delivering shRNA-expressing vectors into tumor cells and eliciting RNAi, thus exerting anti-tumor activity, which may represent a new strategy for the treatment of solid tumors.
研究减毒鼠伤寒沙门氏菌（S typhimurium）能否作为一种抗癌药物或肿瘤靶向载体，将表达 shRNA 的 pDNA 递送至小鼠肿瘤模型中的癌细胞。
使用表达 GFP 的小鼠膀胱移行细胞癌细胞系（BTT-T739），其中 GFP 的表达水平作为 RNA 干扰（RNAi）的指标。用携带针对 GFP 的 shRNA 或乱序 shRNA 表达质粒的 S typhimurium 处理携带 BTT-T739-GFP 肿瘤的小鼠（4-6 周）。细菌给药后 5 天评估 GFP 的 mRNA 和蛋白表达水平，并评估 S typhimurium 的抗肿瘤作用。
在 BTT-T739-GFP 荷瘤小鼠中，S typhimurium（1×10(9)cfu，po）优先在肿瘤中积累长达 40 天，并形成肿瘤与正常组织的比值超过 1000/1。携带针对 GFP 的 shRNA 表达质粒的 S typhimurium 抑制肿瘤细胞中 GFP 的表达达 73.4%。口服给予 S typhimurium 可显著延缓肿瘤生长并延长荷瘤小鼠的存活时间。
本研究表明，减毒 S typhimurium 可用于将表达 shRNA 的载体递送至肿瘤细胞并引发 RNAi，从而发挥抗肿瘤活性，这可能代表治疗实体瘤的一种新策略。
