ABSTRACT

Adenoviral vectors are superior to plasmid vectors in their gene transport efficiency. The A subunit of the diphtheria toxin (DTA) gene is a popular suicide gene in cancer gene therapy. However, DTA is seldom used in adenoviral therapy due to its great toxicity. The toxicity of DTA is so great that even a single molecule of DTA is enough to kill one cell. To avoid this highly toxic effect on normal cells, DTA should be controlled by tumor-specific promoters. The survivin promoter is a widely used tumor-specific promoter. But genes driven by the survivin promoter show a low level of basal gene expression in non-cancer cells. DTA driven by the survivin promoter in adenoviral vectors may be highly toxic not only to cancer cells but also to normal cells. Therefore, DTA should be attenuated when it is used in adenoviral vectors driven by the survivin promoter. In this study, we compared the three kinds of recombinant adenoviruses that carry DTA or its attenuated forms (DTA176 and DTA197) in the treatment of human lung cancer. The results showed that in comparison with both DTA and DTA176, DTA197 is more suitable for adenoviral cancer therapy controlled by the survivin promoter. In addition, Adsur-DTA197 (DTA197 delivered by an adenoviral vector with the survivin promoter) sensitized human lung cancer cells to cisplatin both in vitro and in vivo. These results indicated that Adsur-DTA197 may be a potential chemosensitizer in cancer therapy.

摘要

腺病毒载体的基因转运效率优于质粒载体。白喉毒素 (DTA) 基因的 A 亚基是癌症基因治疗中流行的自杀基因。然而，DTA因其毒性大而很少用于腺病毒治疗。DTA的毒性如此之大，以至于即使是单个DTA分子也足以杀死一个细胞。为了避免这种对正常细胞的剧毒作用，DTA 应该由肿瘤特异性启动子控制。存活蛋白启动子是一种广泛使用的肿瘤特异性启动子。但是由存活蛋白启动子驱动的基因在非癌细胞中表现出低水平的基础基因表达。由腺病毒载体中的存活蛋白启动子驱动的 DTA 可能不仅对癌细胞而且对正常细胞都有剧毒。所以，当 DTA 用于由存活蛋白启动子驱动的腺病毒载体时，它应该被减毒。在这项研究中，我们比较了三种携带 DTA 或其减毒形式（DTA176 和 DTA197）的重组腺病毒在治疗人肺癌中的作用。结果表明，与DTA和DTA176相比，DTA197更适合于survivin启动子控制的腺病毒癌症治疗。此外，Adsur-DTA197（由带有存活蛋白启动子的腺病毒载体递送的 DTA197）使人肺癌细胞对顺铂敏感 DTA197更适合于survivin启动子控制的腺病毒癌症治疗。此外，Adsur-DTA197（由带有存活蛋白启动子的腺病毒载体递送的 DTA197）使人肺癌细胞对顺铂敏感 DTA197更适合于survivin启动子控制的腺病毒癌症治疗。此外，Adsur-DTA197（由带有存活蛋白启动子的腺病毒载体递送的 DTA197）使人肺癌细胞对顺铂敏感体外和体内。这些结果表明 Adsur-DTA197 可能是癌症治疗中潜在的化学增敏剂。