Guo, X., Evans, T.R.J., Somanath, S., Armesilla, A.L., Darling, J.L., Schatzlein, A.G., Cassidy, J. and Wang, W. (2007) In vitro evaluation of cancer-specific NF-κB-CEA enhancer–promoter system for 5-fluorouracil prodrug gene therapy in colon cancer cell lines. British Journal of Cancer, 97 (6). pp. 745-754. 10.1038/sj.bjc.6603930.
Full text not available from this repository.
Nuclear factor-kappa B (NF-κB) is a transcription factor with high transcriptional activity in cancer cells. In this study, we developed a novel enhancer-promoter system, κB4-CEA205, in which the basal carcinoembryonic antigen (CEA) promoter sequence (CEA205) was placed downstream of the four tandem-linked NF-κB DNA-binding sites (κB4). In combination with a κB4 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 κB4-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, κB4, κB4-CEA205 and CMV promoters, respectively. TP protein and enzyme activity were detected at comparable levels in κB4-CEA205- and CMV-driven TP cDNA-transfected cancer cell lines (H630 and RKO). The κB4-TP and CEA205-TP-transfected cell lines, respectively, only demonstrated negligible and low levels of TP protein and enzyme activity. Both CMV- and κB4-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 κB4- and CEA205-driven TP cDNA-transfected cells. The bystander killing effect of CMV- and κB4-CEA205-driven TP cDNA-transfected cells was comparable. This is the first report that indicates that the NF-κB DNA-binding site could be used as a novel cancer-specific enhancer to improve cancer-specific promoter activity in gene-directed enzyme prodrug therapy
|Uncontrolled Keywords:||CEA; Colorectal cancer; GDEPT; NF-κB; Thymidine phosphorylase|
|Departments, units and centres:||Department of Pharmaceutical and Biological Chemistry > Department of Pharmaceutical and Biological Chemistry|
|Journal or Publication Title:||British Journal of Cancer|
|Deposited By:||Library Staff|
|Deposited On:||24 Feb 2012 17:35|
|Last Modified:||24 Feb 2012 17:35|
Item downloaded times since 24 Feb 2012 17:35.
Repository Staff Only: Item control page
School of Pharmacy Staff Only: Edit a copy to replace this item