Malignant pleural mesothelioma-targeted CREBBP/EP300 inhibitory protein 1 promoter system for gene therapy and virotherapy
Malignant pleural mesothelioma-targeted CREBBP/EP300 inhibitory protein 1 promoter system for gene therapy and virotherapy
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DOI：
10.1158/0008-5472.can-08-0047
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发表时间：
2008-09-01
期刊：
影响因子：
11.2
通讯作者：
Tanaka, Noriaki
中科院分区：
文献类型：
--
作者：
Fukazawa, Takuya;Matsuoka, Junji;Tanaka, Noriaki
基因治疗和病毒治疗是治疗恶性胸膜间皮瘤的方法之一。为了提高靶向恶性间皮瘤细胞的效率，我们设计了一种新的系统，使用CREBBP/EP 300抑制蛋白1（CRI 1）的启动子，一种在恶性胸膜间皮瘤中特异性表达的基因。CRI 1启动子的四个串联重复序列（CRI 1（-138）（4x））在恶性胸膜间皮瘤细胞中引起显著高的启动子活性，但在正常间皮瘤细胞和正常成纤维细胞中几乎没有启动子活性。表达由CRI 1（-138 4x）启动子驱动的促凋亡BH 3相互作用死亡激动剂或早期区域1A的重组腺病毒载体在恶性间皮瘤细胞中诱导细胞死亡，但在正常细胞中不诱导细胞死亡。此外，这些病毒在间皮瘤异种移植小鼠模型中显示出抗肿瘤作用。在这里，我们描述了一种新的策略，以针对恶性间皮瘤使用CRI 1（-138 4x）启动子系统。
Gene therapy and virotherapy are one of the approaches used to treat malignant pleural mesothelioma. To improve the efficiency of targeting malignant mesothelioma cells-, we designed a novel system using the promoter of the CREBBP/EP300 inhibitory protein 1 (CRI1), a gene specifically expressed in malignant pleural mesothelioma. Four tandem repeats of the CRI1 promoter (CRI1(-138) (4x)) caused significantly high promoter activity in malignant pleural mesothelioma cells but little promoter activity in normal mesothelial cells and normal fibroblasts. The recombinant adenoviral vector expressing proapoptotic BH3-interacting death agonist or early region 1A driven by the CRI1(-138 4x) promoter induced cell death in malignant mesothelioma cells but not in normal cells. Moreover, these viruses showed antitumor effects in a mesothelioma xenograft mouse model. Here, we describe a novel strategy to target malignant mesothelioma using the CRI1(-138 4x) promoter system.