Tumour-targeted delivery of TRAIL using Salmonella typhimurium enhances breast cancer survival in mice.
Tumour-targeted delivery of TRAIL using Salmonella typhimurium enhances breast cancer survival in mice.
复制标题
DOI：
10.1038/sj.bjc.6605403
复制
发表时间：
2009-11-17
影响因子：
8.8
通讯作者：
中科院分区：
文献类型：
--
作者：
有效的癌症治疗必须选择性地靶向肿瘤，全身毒性最小。使用鼠伤寒沙门氏菌表达细胞毒性蛋白将能够实现递送的空间和时间控制，因为这些细菌优先靶向肿瘤而不是正常组织。我们设计了非致病性S.在原核辐射诱导型RecA启动子的控制下，鼠伤寒杆菌分泌鼠TNF相关凋亡诱导配体（TRAIL）。RecA启动子对辐射的反应用荧光法和免疫印迹法测定。使用流式细胞术和通过测量半胱天冬酶-3活化来确定TRAIL毒性。使用同基因鼠肿瘤模型来确定细菌积累和对表达的TRAIL的响应。辐照后，工程菌S.鼠伤寒沙门氏菌分泌的TRAIL可引起培养的4 T1乳腺癌细胞中caspase-3介导的凋亡和死亡。全身注射沙门氏菌和使用2戈伊γ-照射诱导TRAIL表达导致乳腺肿瘤生长显著延迟，与照射对照相比，死亡风险降低76%。重复给予携带TRAIL的沙门氏菌并结合辐射将30天存活率从0提高到100%。这些结果显示了S.鼠伤寒沙门氏菌作为TRAIL表达载体，其有效地减少肿瘤生长并延长宿主存活。
An effective cancer therapeutic must selectively target tumours with minimal systemic toxicity. Expression of a cytotoxic protein using Salmonella typhimurium would enable spatial and temporal control of delivery because these bacteria preferentially target tumours over normal tissue. We engineered non-pathogenic S. typhimurium to secrete murine TNF-related apoptosis-inducing ligand (TRAIL) under the control of the prokaryotic radiation-inducible RecA promoter. The response of the RecA promoter to radiation was measured using fluorometry and immunoblotting. TRAIL toxicity was determined using flow cytometry and by measuring caspase-3 activation. A syngeneic murine tumour model was used to determine bacterial accumulation and the response to expressed TRAIL. After irradiation, engineered S. typhimurium secreted TRAIL, which caused caspase-3-mediated apoptosis and death in 4T1 mammary carcinoma cells in culture. Systemic injection of Salmonella and induction of TRAIL expression using 2 Gy γ-irradiation caused a significant delay in mammary tumour growth and reduced the risk of death by 76% when compared with irradiated controls. Repeated dosing with TRAIL-bearing Salmonella in conjunction with radiation improved the 30-day survival from 0 to 100%. These results show the pre-clinical utility of S. typhimurium as a TRAIL expression vector that effectively reduces tumour growth and extends host survival.
登录
查看更多内容
APO2L/TRAIL对SCID小鼠中异种移植物的胰腺腺癌患者胰腺腺癌的抗肿瘤作用。
影响因子：
7.4
作者：
Hylander, BL;Pitoniak, R;Penetrante, RB;Gibbs, JF;Oktay, D;Cheng, JR;Repasky, EA
通讯作者：
Repasky, EA
影响因子：
2.1
作者：
Barbé, S;Van Mellaert, L;Anné, J
通讯作者：
Anné, J
影响因子：
3.7
作者：
McLoughlin, JM;McCarty, TM;Kuhn, JA
通讯作者：
Kuhn, JA
影响因子：
5.1
作者：
Lemmon, MJ;vanZijl, P;Brown, JM
通讯作者：
Brown, JM
影响因子：
64.8
作者：
McClelland, M;Sanderson, KE;Wilson, RK
通讯作者：
Wilson, RK