Drug‐regulatable cancer cell death induced by BID under control of the tissue‐specific, lung cancer‐targeted TTS promoter system
Drug‐regulatable cancer cell death induced by BID under control of the tissue‐specific, lung cancer‐targeted TTS promoter system
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DOI：
10.1002/ijc.24584
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发表时间：
2009-10
影响因子：
6.4
通讯作者：
T. Fukazawa;Yutaka Maeda;J. Matsuoka;N. Tanaka;Hirotoshi Tanaka;M. Durbin;Y. Naomoto
中科院分区：
文献类型：
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作者：
T. Fukazawa;Yutaka Maeda;J. Matsuoka;N. Tanaka;Hirotoshi Tanaka;M. Durbin;Y. Naomoto
基因疗法和病毒疗法是目前用于治疗肺癌的方法。癌症基因治疗的成功取决于在不影响正常细胞和组织的情况下，可以选择性地靶向和摧毁不同类型的肿瘤。之前，我们描述了一个我们设计的启动子系统（TTS），它专门针对肺癌细胞，但不影响其他类型的细胞，包括干细胞。在我们的研究中，我们通过在TTS启动子系统（TTS/Bid）中插入促凋亡基因BH3结构域相互作用死亡激动剂（Bid）来增强TTS系统的效用，以创建一种药物调节的肺癌特异性基因疗法。采用重组腺病毒载体将TTS/Bid （Ad‐TTS/Bid）导入肺癌细胞。在A549肺腺癌细胞中有BID的表达和凋亡，而在MCF7乳腺癌细胞和正常人肺成纤维细胞中几乎没有BID的表达和凋亡。顺铂的使用增强了全长BID到t - BID的加工，这显著增加了肺癌特异性细胞死亡。在体内实验中，在肺癌异种移植小鼠模型中，腹腔内注射顺铂增强了载体的抗肿瘤作用。此外，地塞米松在体外和体内均能有效抑制外源性BID的表达和Ad‐TTS/ BID的抗肿瘤作用。在这里，我们描述了使用顺铂和地塞米松与抗肺癌启动子系统（Ad‐TTS/Bid）作为一种安全有效的晚期肺癌基因治疗的疗效。©2009 uicc
Gene therapy and virotherapy are among the approaches currently being used to treat lung cancer. The success of cancer gene therapy depends on treatments where different types of tumors can be selectively targeted and destroyed without affecting normal cells and tissue. Previously, we described a promoter system (TTS) that we designed that is specifically targeted to lung cancer cells but which does not affect other types of cells including stem cells. In our study, we have enhanced the utility of the TTS system by inserting the pro‐apoptotic gene BH3 domain interacting death agonist (Bid) into the TTS promoter system (TTS/Bid) to create a drug regulatable lung cancer‐specific gene therapy. A recombinant adenoviral vector was used to introduce TTS/Bid (Ad‐TTS/Bid) into lung cancer cells. BID expression and apoptosis occurred in A549 pulmonary adenocarcinoma cells but little Bid expression or apoptosis occurred in MCF7 breast cancer cells or in normal human lung fibroblasts. The use of cisplatin enhanced the processing of full length BID to t‐BID which significantly increased lung cancer‐specific cell death. In in vivo experiments, intraperitonal injection of cisplatin enhanced the antitumor effects of the vector in a lung cancer xeno‐graft mouse model. Moreover, dexamethasone effectively suppressed exogenous BID expression and the antitumor effect of Ad‐TTS/Bid both in vitro and in vivo. Here, we describe the efficacy of the use of cisplatin and dexamethasone with the anti lung cancer promoter system (Ad‐TTS/Bid) for a safe and effective gene therapy against advanced lung cancer. © 2009 UICC