Targeting advanced non small cell lung cancer in vivo by pulmonary surfactant -adenovirus-mediated gene transfer

通过肺表面活性物质-腺病毒介导的基因转移体内靶向晚期非小细胞肺癌

• 批准号: 20390369
• 负责人: MATSUOKA Jyunji
• 金额: $ 12.65万
• 依托单位: Okayama University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2008
• 资助国家: 日本
• 起止时间: 2008 至 2010
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-20390369/
• 关键词: surfactant protein; non small cell lung cancer; adenovirus; KRas; intratracheal administration; TTF1; 肺癌; Surfactant protein A; Thyriod transcription factor 1; グルココルチコイド; cisplatin; 制限増殖アデノウイルス; 肺胞サーファクタント; Thyroid transcription factor 1; 進行

Pulmonary surfactant has been used as a carrier to deliver a therapeutic virus to dysfunctional lung cells that reside within an intricate lung structure. To investigate whether pulmonary surfactant enhances the efficacy of intratracheal instillation of a therapeutic virus to target advanced non small cell lung cancer in vivo, we developed a recombinant adenovirus that induces cell death only in lung cancer cells and injected the adenovirus into an advanced lung cancer model mouse intratracheally with or without surfactant. A therapeutic adenovirus that induces cell death only in lung cancer cells was constructed by combining a lung cancer specific promoter fused to cytotoxic E1A. This adenovirus was intratracheally injected into the KRAS or KRASlung cancer model mice (CCSP-rtTA/Tet-op・K-Ras4bG12D bitransgenic mice or CCSP-rtTA/Tet-op・K-Ras4bG12D・p53- tripletransgenic mice) in the presence/absence of pulmonary surfactant. Intratracheally-injected therapeutic adenovirus with pulmonary surfactant spread to airways as well as to the alveolar region of the lung and caused reduction of lung tumors developed in the lung cancer model mice. The therapeutic adenovirus without pulmonary surfactant spread only to airways and had ten times less effectiveness in tumor reduction. Here, we demonstrate that pulmonary surfactant is an efficient tool to intratracheally deliver a therapeutic virus to treat advanced lung cancer in vivo.

肺表面活性剂已被用作载体，将治疗性病毒递送至存在于复杂肺结构内的功能失调的肺细胞。为了研究肺表面活性物质是否能增强肺内滴注治疗性病毒对体内晚期非小细胞肺癌的疗效，我们开发了一种仅诱导肺癌细胞死亡的重组腺病毒，并将该腺病毒注射到晚期肺癌模型小鼠体内，无论是否有表面活性物质。通过将肺癌特异性启动子与细胞毒性E1 A融合，构建了仅在肺癌细胞中诱导细胞死亡的治疗性腺病毒。将该腺病毒分别注入KRAS或KRAS肺癌模型小鼠（CCSP-rtTA/Tet-op·K-Ras 4 bG 12 D双转基因小鼠或CCSP-rtTA/Tet-op·K-Ras 4 bG 12 D·p53-三联转基因小鼠），在肺表面活性物质存在或不存在的情况下进行实验。经气管内注射的治疗性腺病毒与肺表面活性剂一起扩散到气道以及肺的肺泡区域，并导致肺癌模型小鼠中发生的肺肿瘤减少。不含肺表面活性物质的治疗性腺病毒仅扩散到气道，并且在肿瘤缩小方面的效果低十倍。在这里，我们证明了肺表面活性物质是一种有效的工具，在体内提供治疗性病毒治疗晚期肺癌。

项目成果

Targeting KRAS mutation-bearing lung cancer in vivo by pulmonary surfactant-adenovirus-mediated gene transfer.

• 发表时间: 2010-12
• 期刊: Anticancer research
• 影响因子: 2
• 作者: T. Fukazawa;Yutaka Maeda;J. Matsuoka;T. Ono;K. Mominoki;T. Yamatsuji;Kaoru Shigemitsu;I. Morita;I. Murakami;Hirotoshi Tanaka;M. Durbin;Y. Naomoto

肺胞サーファクタントを用いたKRAS変異肺癌を標的とする新規ウイルス療法の開発

使用肺泡表面活性剂开发针对 KRAS 突变肺癌的新型病毒疗法

• 发表时间: 2010
• 作者: Miyoshi N;Ishii H;Nagai K;Hoshino H;Mimori K;Tanaka F;Nagano H;Sekimoto M;Doki Y;Mori M;深澤拓也
• 通讯作者: 深澤拓也

Drug‐regulatable cancer cell death induced by BID under control of the tissue‐specific, lung cancer‐targeted TTS promoter system

• DOI: 10.1002/ijc.24584
• 发表时间: 2009-10
• 期刊: International Journal of Cancer
• 影响因子: 6.4
• 作者: T. Fukazawa;Yutaka Maeda;J. Matsuoka;N. Tanaka;Hirotoshi Tanaka;M. Durbin;Y. Naomoto