Suicidal gene therapy in an NF-κB-controlled tumor environment as monitored by a secreted blood reporter

被引：13

作者：

Badr, C. E. ^{[1
,2
,3
]}

Niers, J. M. ^{[1
,2
,3
]}

Morse, D. ^{[1
,2
]}

Koelen, J. A. ^{[1
,2
,4
]}

Vandertop, P. ^{[3
]}

Noske, D. ^{[3
]}

Wurdinger, T. ^{[3
]}

Zalloua, P. A. ^{[5
]}

Tannous, B. A. ^{[1
,2
,6
]}

机构：

[1] Massachusetts Gen Hosp, Ctr Neurosci, Dept Neurol, Boston, MA 02129 USA

[2] Harvard Univ, Sch Med, Neurosci Program, Boston, MA 02115 USA

[3] Canc Ctr Amsterdam, VU Med Ctr, Dept Neurosurg, Neurooncol Res Grp, Amsterdam, Netherlands

[4] Univ Utrecht, Grad Sch Life Sci, Utrecht, Netherlands

[5] Lebanese Amer Univ, Sch Med, Chouran Beirut, Lebanon

[6] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Mol Imaging Res, Boston, MA USA

来源：

GENE THERAPY | 2011年 / 18卷 / 05期

关键词：

suicidal gene therapy; cytosine deaminase; uracil phosphoribosyltransferase; nuclear factor-kappa B; Gaussia luciferase; blood reporter; CYTOSINE DEAMINASE GENE; ENZYME-PRODRUG THERAPY; CELL LUNG-CANCER; IN-VIVO; URACIL PHOSPHORIBOSYLTRANSFERASE; COLORECTAL-CANCER; OVARIAN-CANCER; EXPRESSION; 5-FLUOROCYTOSINE; ACTIVATION;

D O I：

10.1038/gt.2010.156

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

The nuclear factor-kappa B (NF-kappa B) 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-kappa B-based reporter system (five tandem repeats of NF-kappa B responsive genomic element (NF; 14 bp 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 (NE-CU-IGIuc). We showed that malignant tumor cells have high expression of Gluc, which correlates to high activation of NF-kappa B. When NF-kappa B was further activated by tumor necrosis factor-a 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. Gene Therapy (2011) 18, 445-451; doi:10.1038/gt.2010.156; published online 9 December 2010

引用

页码：445 / 451

页数：7

共 53 条

[1]

Experimental gene therapy for brain tumors using adenovirus-mediated transfer of cytosine deaminase gene and uracil phosphoribosyltransferase gene with 5-fluorocytosine [J].