Suicidal gene therapy in an NF-κB-controlled tumor environment as monitored by a secreted blood reporter.
Suicidal gene therapy in an NF-κB-controlled tumor environment as monitored by a secreted blood reporter.
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作者：
核因子-κB（NF-κB）已知在许多癌症类型中被激活，包括肺癌、卵巢癌、星形细胞瘤、黑素瘤、前列腺癌以及胶质母细胞瘤，并且已显示与疾病进展相关。我们克隆了一种新的基于NF-κ B的报告系统（NF-κB响应基因组元件的五个串联重复（NF;每个14 bp）），以驱动酵母胞嘧啶脱氨酶和尿嘧啶磷酸核糖基转移酶（CU）之间的融合表达盒（作为治疗基因）和分泌的Gaussia荧光素酶（Gluc）（作为血液报告基因），由内部核糖体进入位点（NF-CU-IGluc）分开。我们发现恶性肿瘤细胞具有Gluc的高表达，这与NF-κB的高活化相关。当NF-κB在这些细胞中被肿瘤坏死因子-α进一步激活时，我们观察到Gluc水平增加高达10倍，因此在培养的细胞和体内皮下肿瘤异种移植模型中，人胶质瘤细胞中的转基因表达大大增强了这些细胞对前药5-氟胞嘧啶的敏感性。这种诱导系统提供了一种工具，以提高癌症治疗的成像和治疗基因的表达。
The nuclear factor-κB (NF-κB) is known to be activated in many cancer types including lung, ovarian, astrocytomas, melanoma, prostate as well as glioblastoma, and has been shown to correlate with disease progression. We have cloned a novel NF-κB-based reporter system (five tandem repeats of NF-κB responsive genomic element (NF; 14bp each)) to drive the expression cassette for both a fusion between the yeast cytosine deaminase and uracil phosphoribosyltransferase (CU) as a therapeutic gene and the secreted Gaussia luciferase (Gluc) as a blood reporter, separated by an internal ribosomal entry site (NF-CU-IGluc). We showed that malignant tumor cells have high expression of Gluc, which correlates to high activation of NF-κB. When NF-κB was further activated by tumor necrosis factor-α in these cells, we observed up to 10-fold increase in Gluc levels and therefore transgene expression in human glioma cells served to greatly enhance the sensitization of these cells to the prodrug, 5-fluorocytosine both in cultured cells and in vivo subcutaneous tumor xenograft model. This inducible system provides a tool to enhance the expression of imaging and therapeutic genes for cancer therapy.
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DOI：
10.1016/j.bbrc.2006.03.015
发表时间：
2006-05-05
影响因子：
3.1
作者：
Greenberg, H;Ye, XB;Liu, SF
通讯作者：
Liu, SF
DOI：
10.1111/j.1432-1033.1992.tb16604.x
发表时间：
1992-02-15
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
ANDERSEN, PS;SMITH, JM;MYGIND, B
通讯作者：
MYGIND, B
影响因子：
64.5
作者：
CHUNG, JH;WHITELEY, M;FELSENFELD, G
通讯作者：
FELSENFELD, G
影响因子：
6.2
作者：
Briat, Arnaud;Vassaux, Georges
通讯作者：
Vassaux, Georges
影响因子：
4.2
作者：
HIRSCHOWITZ, EA;OHWADA, A;CRYSTAL, RG
通讯作者：
CRYSTAL, RG