| Autor: |
Guo, X., Evans, T. R. J., Somanath, S., Armesilla, A. L., Darling, J. L., Schatzlein, A., Cassidy, J., Wang, W. |
| Předmět: |
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| Zdroj: |
British Journal of Cancer; 9/17/2007, Vol. 97 Issue 6, p745-754, 10p, 1 Diagram, 3 Charts, 4 Graphs |
| Abstrakt: |
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.British Journal of Cancer (2007) 97, 745–754. doi:10.1038/sj.bjc.6603930 www.bjcancer.com Published online 7 August 2007 [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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