Adenoviral targeting of gene expression to tumors.
Adenoviral targeting of gene expression to tumors.
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DOI：
10.1038/cgt.2010.1
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发表时间：
2010-06
影响因子：
6.4
通讯作者：
中科院分区：
文献类型：
--
作者：
利用生物化学、成像和组织学方法，我们采用转录靶向技术来增加静脉注射重组腺病毒载体在体内肿瘤基因表达的特异性。令人惊讶的是，通过简单地降低病毒剂量，组成型表达重组腺病毒AdCMVLuc的肿瘤表达与其他组织相比的相对特异性增加。然而，即使在较低的剂量下，使用组成型启动子在肝脏中的高频率的病毒感染和转基因表达仍然是一个实质性的问题。为了进一步增强肿瘤特异性，我们构建了一系列腺病毒表达荧光素酶从几个其他的启动子，并测试其选择性转录基因在肿瘤细胞在体外和体内的能力。组成型活性病毒启动子（RSV、SRα）的肿瘤选择性差异很大，但低氧应答启动子（碳酸酐酶9、派-1、SOD 2和几种嵌合构建体）表现出最大的肿瘤选择性表达。我们的研究结果表明，肿瘤靶向HT 1080纤维肉瘤很容易实现使用转录靶向机制。我们将体内HT 1080肿瘤中相对高水平的基因转移和表达归因于病毒进入肿瘤的增加，这可能是由于肿瘤血管系统的不连续性以及缺氧和炎症肿瘤微环境中应激反应启动子的表达增强。
Using biochemical, imaging and histological methods, we employed transcriptional targeting to increase the specificity of tumor gene expression in vivo for intravenously administered recombinant adenovirus vectors. Surprisingly, the relative specificity of tumor expression in comparison to other tissues was increased for a constitutively expressing recombinant adenovirus, AdCMVLuc, by simply reducing the viral dose. Even at lower doses, however, the high frequency of viral infection and transgene expression in the liver using constitutive promoters still represents a substantial problem. To further augment tumor specificity, we constructed a series of adenoviruses expressing luciferase from several other promoters and tested their ability to selectively transcribe genes in tumor cells both in vitro and in vivo. Constitutively active viral promoters (RSV, SRα) varied widely in their tumor selectivity, but hypoxia-responsive promoters (carbonic anhydrase 9, PAI-1, SOD2, and several chimeric constructs) demonstrated the most tumor-selective expression. Our results show that tumor targeting to HT1080 fibrosarcomas was readily achieved using transcriptional targeting mechanisms. We attribute the relatively high level of gene transfer and expression in HT1080 tumors in vivo to increased viral access to the tumor, presumably due to discontinuities in tumor vasculature and augmented expression from stress-responsive promoters in the hypoxic and inflammatory tumor microenvironment.
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影响因子：
5.1
作者：
Modlich, U;Pugh, CW;Bicknell, R
通讯作者：
Bicknell, R
影响因子：
4.4
作者：
Dioum, Elhadji M.;Clarke, Stephen L.;Garcia, Joseph A.
通讯作者：
Garcia, Joseph A.
DOI：
10.1111/j.1600-0463.2008.01148.x
发表时间：
2008-07
期刊：
APMIS : acta pathologica, microbiologica, et immunologica Scandinavica
影响因子：
--
作者：
Fukumura D;Jain RK
通讯作者：
Jain RK
影响因子：
5.1
作者：
Binley, K;Askham, Z;Naylor, S
通讯作者：
Naylor, S
影响因子：
6.4
作者：
Chen, JS;Liu, JC;Hung, MC
通讯作者：
Hung, MC