論文 - 詳細
| RRC ID | 11037 |
|---|---|
| 著者 | Suzuki T, Sakurai F, Nakamura S, Kouyama E, Kawabata K, Kondoh M, Yagi K, Mizuguchi H. |
| タイトル | miR-122a-regulated expression of a suicide gene prevents hepatotoxicity without altering antitumor effects in suicide gene therapy. |
| ジャーナル | Mol Ther |
| Abstract |
The combined use of adenovirus (Ad) vectors expressing herpes simplex virus thymidine kinase (HSVtk) and ganciclovir (GCV) offers a potential therapeutic strategy against cancer. However, intratumorally injected Ad vectors are disseminated into the systemic circulation and efficiently transduce the liver, resulting in severe hepatotoxicity. In order to overcome this problem, an Ad vector carrying a microRNA (miRNA)-regulated expression system was developed by inserting into the 3'-untranslated region (3'-UTR) of the expression cassette four tandem copies of sequences with perfect complementarity to miR-122a, which exhibits liver-specific expression. Transgene expression from the Ad vector carrying the miR-122a target sequences was 7- to 70-fold lower in cells with high miR-122a expression as compared to expression from a conventional Ad vector. Intratumoral injection of the Ad vector containing the miR-122a target sequences resulted in a 130- to 1,500-fold reduction in hepatic transgene products (without affecting the transgene expression in the tumor) when compared with those from a conventional Ad vector. In suicide gene therapy, the inclusion of the miR-122a target sequences in the HSVtk expression cassette achieved not only significant antitumor effects, but also a dramatic reduction in HSVtk/GCV-induced hepatotoxicity. These results indicate that Ad vectors that mediate miR-122a-regulated HSVtk expression provide a safe and efficient suicide gene therapy strategy. |
| 巻・号 | 16(10) |
| ページ | 1719-26 |
| 公開日 | 2008-10-1 |
| DOI | 10.1038/mt.2008.159 |
| PII | S1525-0016(16)32076-7 |
| PMID | 18665157 |
| MeSH | 3' Untranslated Regions Adenoviridae / genetics Animals Female Gene Expression Regulation / physiology* Genes, Transgenic, Suicide* Genetic Therapy* Genetic Vectors Humans Mice Mice, Inbred C57BL MicroRNAs / physiology* Simplexvirus / enzymology Thymidine Kinase / genetics |
| IF | 8.986 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | Patent(IFI CLAIMS) |
| 各媒体での言及数の合計 | 38 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 3.0 |
| リソース情報 | |
| ヒト・動物細胞 | HuH-7(RCB1366) 293(RCB1637) B16 melanoma(RCB1283) |