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首页> 外文期刊>Cancer science. >p53 activated by AND gate genetic circuit under radiation and hypoxia for targeted cancer gene therapy
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p53 activated by AND gate genetic circuit under radiation and hypoxia for targeted cancer gene therapy

机译：放射线和缺氧条件下，AND门遗传电路激活p53用于靶向癌症基因治疗

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Radio-activated gene therapy has been developed as a novel therapeutic strategy against cancer; however, expression of therapeutic gene in peritumoral tissues will result in unacceptable toxicity to normal cells. To restrict gene expression in targeted tumor mass, we used hypoxia and radiation tolerance features of tumor cells to develop a synthetic AND gate genetic circuit through connecting radiation sensitivity promoter cArG(6), heat shock response elements SNF1, HSF1 and HSE4 with retroviral vector plxsn. Their construction and dynamic activity process were identified through downstream enhanced green fluorescent protein and wtp53 expression in non-small cell lung cancer A549 cells and in a nude mice model. The result showed that AND gate genetic circuit could be activated by lower required radiation dose (6 Gy) and after activated, AND gate could induce significant apoptosis effects and growth inhibition of cancer cells in vitro and in vivo. The radiation- and hypoxia-activated AND gate genetic circuit, which could lead to more powerful target tumoricidal activity represented a promising strategy for both targeted and effective gene therapy of human lung adenocarcinoma and low dose activation character of the AND gate genetic circuit implied that this model could be further exploited to decrease side-effects of clinical radiation therapy.
机译：放射性基因疗法已被开发为一种针对癌症的新型治疗策略。然而，治疗基因在肿瘤周围组织中的表达将导致对正常细胞的不可接受的毒性。为了限制目标肿瘤群中的基因表达，我们利用肿瘤细胞的低氧和辐射耐受特性，通过将辐射敏感性启动子cArG（6），热休克反应元件SNF1，HSF1和HSE4与逆转录病毒载体plxsn连接起来，建立了一个合成的AND门遗传电路。 。通过下游增强的绿色荧光蛋白和wtp53在非小细胞肺癌A549细胞和裸鼠模型中的表达，确定了它们的构建和动态活性过程。结果表明，通过较低的辐射剂量（6 Gy）可以激活与门遗传电路，并且在激活后，与门可以在体内外诱导明显的凋亡作用并抑制癌细胞的生长。辐射和缺氧激活的AND门遗传电路可能导致更强大的靶标杀伤活性，这代表了针对人肺腺癌的靶向和有效基因治疗的有前途的策略，并且AND门遗传电路的低剂量激活特性暗示了这一点。该模型可进一步用于减少临床放射治疗的副作用。

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