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| Item Type: | Article |
|---|---|
| Title: | Complete in vivo reversal of the multidrug resistance phenotype by jet-injection of anti-MDR1 short hairpin RNA-encoding plasmid DNA |
| Creators Name: | Stein, U., Walther, W., Stege, A., Kaszubiak, A., Fichtner, I. and Lage, H. |
| Abstract: | Triggering the RNA interference (RNAi) pathway by inducing the expression of short hairpin RNA (shRNA) molecules has become a promising tool for efficient silencing of a given gene in gene therapy applications. In this study, shRNA encoding DNA was utilized to reverse the classical MDR1/P-glycoprotein (MDR1/P-gp)-mediated multidrug resistance (MDR) phenotype in vivo. For the first time, the nonviral jet-injection technology was applied for delivering naked shRNA-vector constructs for direct intratumoral in vivo transfer. The highly efficient anti-MDR1 shRNA expression vectors were applied twice in the human MDR1/P-gp overexpressing MaTu/ADR cancer xenograft-bearing mice, and twice in the corresponding drug-sensitive parental MaTu tumor xenograft bearing mice as well. Two days after anti-MDR1 shRNA vector injection, the expression level of the MDR1 messenger RNA (mRNA) was decreased by more than 90% and the corresponding MDR1/P-gp protein was no longer detectable in the tumors. Two jet-injections of anti-MDR1 shRNA vectors into the tumors, combined with two intravenous (IV) administrations of doxorubicin, were sufficient to achieve complete reversal of the drug-resistant phenotype. The data show that jet-injection delivery of shRNA-expressing vectors is effective in reversing MDR1/P-gp-mediated MDR in vivo, and is therefore a promising strategy for making tumors with an MDR1/Pgp-dependent MDR phenotype revert to a drug-sensitive state. |
| Keywords: | Neoplasm DNA, Multiple Drug Resistance, Neoplasm Drug Resistance, Hela Cells, Intralesional Injections, Jet Injections, Experimental Mammary Neoplasms, P-Glycoprotein, Phenotype Plasmids, Messenger RNA, Neoplasm RNA, Animals, Mice |
| Source: | Molecular Therapy |
| ISSN: | 1525-0016 |
| Publisher: | Nature Publishing Group |
| Volume: | 16 |
| Number: | 1 |
| Page Range: | 178-186 |
| Date: | January 2008 |
| Official Publication: | https://doi.org/10.1038/sj.mt.6300304 |
| PubMed: | View item in PubMed |
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