Targeting KRAS mutation-bearing lung cancer in vivo by pulmonary surfactant-adenovirus-mediated gene transfer.
Targeting KRAS mutation-bearing lung cancer in vivo by pulmonary surfactant-adenovirus-mediated gene transfer.
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发表时间：
2010-12
影响因子：
2
通讯作者：
T. Fukazawa;Yutaka Maeda;J. Matsuoka;T. Ono;K. Mominoki;T. Yamatsuji;Kaoru Shigemitsu;I. Morita;I. Murakami;Hirotoshi Tanaka;M. Durbin;Y. Naomoto
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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
肺表面活性物质已被用作载体，将治疗性病毒输送到位于复杂肺结构中的功能障碍的肺细胞。为了研究肺表面活性物质是否提高了治疗性病毒对体内携带KRAS突变的肺癌的靶向作用，我们开发了一种仅在肺癌细胞中诱导细胞死亡的重组腺病毒，并将该重组腺病毒注射到有或没有表面活性物质的KRAS突变阳性肺癌小鼠模型中。将肿瘤特异性端粒酶逆转录酶(HTERT)启动子融合到CCAAT/增强子结合蛋白α(CEBPα)和修饰的肺特异性Clara细胞特异性10 kDa蛋白(CC10)启动子融合到细胞毒腺病毒5型早期区(E1a)，构建了一种仅在肺癌细胞中诱导细胞死亡的治疗性腺病毒。CEBPα只在癌细胞中诱导，并激活CC10启动子，进而诱导细胞毒性E1a，并在体外仅导致肺癌细胞死亡。在肺表面活性物质存在和不存在的情况下，将重组腺病毒分别经气管给药给模型鼠(CCSP-RTTA/Tet-OP-K-Ras4bG12D双转基因小鼠)。带有肺表面活性物质的治疗性腺病毒经气管内传播到呼吸道以及肺泡区，并导致肺部肿瘤的减少发展。不含肺表面活性物质的治疗性腺病毒只传播到呼吸道，在肿瘤减少方面的效果降低了十分之一。在这里，我们证明了肺表面活性物质是一种有效的工具，可以通过气管内输送治疗性病毒来治疗体内KRAS突变阳性肺癌。
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 KRAS mutation-bearing lung cancer in vivo, we developed a recombinant adenovirus that induces cell death only in lung cancer cells and injected the adenovirus into a mouse model of KRAS mutation-positive lung cancer intratracheally with and without surfactant. A therapeutic adenovirus that induces cell death only in lung cancer cells was constructed by combining a cancer-specific human telomerase reverse transcriptase (hTERT) promoter fused to CCAAT/enhancer-binding protein alpha (CEBPα) with a modified lung-specific Clara cell-specific 10-kDa protein (CC10) promoter fused to cytotoxic adenovirus type 5 early region 1A (E1A). CEBPα is induced only in cancer cells and activates the CC10 promoter, which in turn induces cytotoxic E1A, and causes cell death only in lung cancer cells in vitro. This adenovirus was intratracheally administered to the model mice (CCSP-rtTA/Tet-op-K-Ras4bG12D bitransgenic mice) in the presence and absence of pulmonary surfactant. Intratracheally administered therapeutic adenovirus with pulmonary surfactant spread to airways, as well as to the alveolar region of the lung, and caused a reduction of lung tumors developed. The therapeutic adenovirus without pulmonary surfactant spread only to airways and was ten-fold less effective in tumor reduction. Here, we demonstrate that pulmonary surfactant is an efficient tool to intratracheally deliver a therapeutic virus to treat KRAS mutation-positive lung cancer in vivo.