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Wolverhampton Intellectual Repository and E-Theses > Research Institutes > Research Institute in Healthcare Science > Cancer Research Group > In vitro evaluation of cancer-specific NF-kappaB-CEA enhancer-promoter system for 5-fluorouracil prodrug gene therapy in colon cancer cell lines.

Please use this identifier to cite or link to this item: http://hdl.handle.net/2436/29507
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Title: In vitro evaluation of cancer-specific NF-kappaB-CEA enhancer-promoter system for 5-fluorouracil prodrug gene therapy in colon cancer cell lines.
Authors: Guo, X.
Evans, T.R.J.
Somanath, S.
Armesilla, Angel Luis
Darling, John L.
Schatzlein, A.
Cassidy, James
Wang, Weiguang
Citation: British Journal of Cancer, 97(6): 745-754
Publisher: Nature Publishing Group
Journal: British Journal of Cancer
Issue Date: 2007
URI: http://hdl.handle.net/2436/29507
DOI: 10.1038/sj.bjc.6603930
PubMed ID: 17687334
Additional Links: http://www.nature.com/bjc/journal/v97/n6/abs/6603930a.html
Abstract: Nuclear factor-kappa B (NF-kappaB) is a transcription factor with high transcriptional activity in cancer cells. In this study, we developed a novel enhancer-promoter system, kappaB4-CEA205, in which the basal carcinoembryonic antigen (CEA) promoter sequence (CEA205) was placed downstream of the four tandem-linked NF-kappaB DNA-binding sites (kappaB4). In combination with a kappaB4 enhancer, the transcriptional activity of the CEA promoter was significantly enhanced (three- to eight-fold) in cancer cell lines but not in normal cells. In cancer cell lines, the transcriptional activity of kappaB4-CEA205 was comparable with that of the SV40 promoter. We also constructed vectors in which the thymidine phosphorylase (TP) cDNA was under the control of CEA205, kappaB4, kappaB4-CEA205 and CMV promoters, respectively. TP protein and enzyme activity were detected at comparable levels in kappaB4-CEA205- and CMV-driven TP cDNA-transfected cancer cell lines (H630 and RKO). The kappaB4-TP and CEA205-TP-transfected cell lines, respectively, only demonstrated negligible and low levels of TP protein and enzyme activity. Both CMV- and kappaB4-CEA205-driven TP cDNA transiently transfected cells were 8- to 10-fold sensitised to 5-fluorouracil (5-FU) prodrug, 5'-deoxy-5-fluorouradine (5'-DFUR), in contrast to only 1.5- to 2-fold sensitised by the kappaB4- and CEA205-driven TP cDNA-transfected cells. The bystander killing effect of CMV- and kappaB4-CEA205-driven TP cDNA-transfected cells was comparable. This is the first report that indicates that the NF-kappaB DNA-binding site could be used as a novel cancer-specific enhancer to improve cancer-specific promoter activity in gene-directed enzyme prodrug therapy.
Type: Article
Language: en
Keywords: NF-B
CEA
GDEPT
Thymidine Phosphorylase
Colorectal cancer
Cancer, Colorectal
MeSH: Blotting, Western
Carcinoembryonic Antigen
Cell Line, Tumor
Colonic Neoplasms
Colorectal Neoplasms
Cytomegalovirus
DNA, Complementary
Fluorouracil
Gene Therapy
Humans
NF-kappa B
Prodrugs
Promoter Regions (Genetics)
Reverse Transcriptase Polymerase Chain Reaction
Thymidine Phosphorylase
Transfection
ISSN: 0007-0920
Appears in Collections: Cancer Research Group

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