Hypoxia-mediated tumour targeting
Hypoxia-mediated tumour targeting
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DOI：
10.1038/sj.gt.3301944
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发表时间：
2003-04-01
期刊：
影响因子：
5.1
通讯作者：
Naylor, S
中科院分区：
文献类型：
--
作者：
Binley, K;Askham, Z;Naylor, S
缺氧是肿瘤常见的生理特征。它激活信号级联，最终稳定HIF-1转录因子和激活具有缺氧反应元件（HRE）的基因。我们已经使用了一个优化的缺氧响应启动子（OBHRE），以研究在体内的情况下，腺病毒载体的缺氧靶向基因表达。OBHRE启动子在肝脏或脾脏中显示出有限的活性，使得表达比强CMV/IE启动子驱动的表达低1000倍。然而，在肿瘤微环境中，OBHRE启动子的表达水平与CMV/IE启动子相当。接下来，我们表明表达由OBHRE启动子调节的人细胞色素P450（CYP 2B 6）的腺病毒响应于前药环磷酰胺（CPA）延迟肿瘤生长。最后，我们利用腺病毒的嗜肝性来研究OBHRE启动子在前药更昔洛韦（GCV）的背景下是否可以减轻表达胸苷激酶（TK）的重组腺病毒的肝毒性。高剂量Ad. CMVTK/GCV治疗引起显著的肝坏死，而相同剂量的Ad.HRETK耐受良好。这些体内数据表明，通过OBHRE启动子的低氧靶向基因表达可用于增加细胞毒性癌症基因治疗的治疗窗口。
Hypoxia is a common physiological feature of tumours. It activates a signalling cascade that culminates in the stabilization of the HIF-1 transcription factor and activation of genes that possess a hypoxia response element (HRE). We have used an optimized hypoxia responsive promoter (OBHRE) to investigate hypoxia-targeted gene expression in vivo in the context of an adenovirus vector. The OBHRE promoter showed limited activity in the liver or spleen such that expression was 1000-fold lower than that driven by the strong CMV/IE promoter. However, in the context of the tumour microenvironment, the OBHRE promoter achieved expression levels comparable to that of the CMV/IE promoter. Next, we showed that an adenovirus expressing the human cytochrome P450 (CYP2B6) regulated by the OBHRE promoter delays tumour growth in response to the prodrug cyclophosphamide (CPA). Finally, we exploited the hepatotropism of adenovirus to investigate whether the OBHRE promoter could mitigate the hepatotoxicity of a recombinant adenovirus expressing thymidine kinase (TK) in the context of the prodrug ganciclovir (GCV). High-dose Ad. CMVTK/GCV treatment caused significant liver necrosis whereas the same dose of Ad.HRETK was well tolerated. These in vivo data demonstrate that hypoxia-targeted gene expression via the OBHRE promoter can be used to increase the therapeutic window of cytotoxic cancer gene therapy.