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| Item Type: | Article |
|---|---|
| Title: | Use of the human MDR1 promoter for heat-inducible expression of therapeutic genes |
| Creators Name: | Walther, W., Stein, U. and Schlag, P.M. |
| Abstract: | The promoter of the human multidrug resistance gene (mdr1) harbors stress-responsive elements, which can be induced e.g., by heat or cytostatic drugs. In previous studies the drug-responsiveness of the mdr1 promoter was successfully used for the drug-inducible expression of the human TNF-{alpha} gene in vitro and in vivo. Beside the drug-responsive elements of the mdr1 promoter, heat-shock responsive elements have also been identified, which could be exploited for construction of heat-inducible expression vectors. To analyze the hyperthermia-inducibility of the mdr1 promoter we used the pmdr-p-CAT and pM3mdr-p-hTNF vector constructs. Both constructs carry the mdr1 promoter fragment spanning from - 207 to + 153 to drive expression of the CAT-reporter or TNF-{alpha} gene. We tested the heat-induced CAT-reporter and TNF-{alpha} expression in vitro in transduced HCT15 and HCT116 human colon carcinoma cells. For the studies the transduced tumor cells were treated with hyperthermia at 41.5°C or 43°C for 2 hr to induce CAT or TNF-α expression. Cells and supernatants were harvested before hyperthermia and at certain time points (0-120 hr) after heat shock. The heatinduced CAT-reporter expression or TNF-{alpha} secretion was determined by specific ELISA. The experiments indicate that hyperthermia activates the mdr1 promoter in a temperature and time dependent manner. This induction leads to an 2- to 4-fold increase in CAT-reporter or 2- to 7-fold increase in TNF{alpha} expression in the tumor cell lines. These experiments reveal that the mdr1 promoter driven expression of therapeutic genes can be employed for combined cancer gene therapy approaches. |
| Keywords: | Cancer, Gene Therapy, Hyperthermia, Mdr1 Promoter |
| Source: | International Journal of Cancer |
| ISSN: | 0020-7136 |
| Publisher: | Wiley |
| Volume: | 98 |
| Number: | 2 |
| Page Range: | 291-296 |
| Date: | 1 January 2002 |
| PubMed: | View item in PubMed |
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