論文 - 詳細
| RRC ID | 19610 |
|---|---|
| 著者 | Uchibori R, Okada T, Ito T, Urabe M, Mizukami H, Kume A, Ozawa K. |
| タイトル | Retroviral vector-producing mesenchymal stem cells for targeted suicide cancer gene therapy. |
| ジャーナル | J Gene Med |
| Abstract |
BACKGROUND:Mesenchymal stem cells (MSCs) are a promising vehicle for targeted cancer gene therapy because of their potential of tumor tropism. For efficient therapeutic application, we developed retroviral vector-producing MSCs that enhance tumor transduction via progeny vector production. METHODS:Rat bone marrow-derived MSCs were nucleofected with the proviral plasmids (vesicular stomatitis virus-G protein-pseudotyped retroviral vector components) (VP-MSCs) or pLTR plasmid alone (non-VP-MSCs). The luciferase-based in vivo imaging system was used to assess gene expression periodically. To evaluate the anticancer effects, we administered MSCs expressing herpes simplex virus-thymidine kinase (HSV-tk) into the left ventricular cavity of nude mice engrafted with 9L glioma cells subcutaneously. RESULTS:In vivo imaging revealed that administration of luciferase-expressing non-VP-MSCs enhanced the bioluminescence signal at the inoculation sites of 9L cells, whereas no accumulation was observed in mice at the site of the control Rat-1 fibroblasts. Compared to non-VP-MSCs, the administration of VP-MSCs resulted in significant augmentation of the signal with an increase in transgene copy number. Immunohistochemical analysis showed marked luciferase expression at the tumor periphery in mice injected with VP-MSCs, whereas little expression was detected in those injected with non-VP-MSCs. Under the continuous infusion of ganciclovir, systemic administration of VP-MSCs expressing HSV-tk suppressed tumor growth more effectively than non-VP-MSC administration, whereas no anticancer effect was observed without ganciclovir treatment. Furthermore, VP-MSC administration caused no transgene transduction in the normal tissues and organs. CONCLUSIONS:VP-MSCs accumulated at the site of tumors after intravascular injection in tumor-bearing mice, followed by in situ gene transfer to tumors without transduction of normal organs. When applied to the HSV-tk/ganciclovir suicide gene therapy, more efficient tumor growth suppression was observed using VP-MSCs compared to non-VP-MSCs. This VP-MSC-based system has great potential for improved cancer gene therapy. |
| 巻・号 | 11(5) |
| ページ | 373-81 |
| 公開日 | 2009-5-1 |
| DOI | 10.1002/jgm.1313 |
| PMID | 19274675 |
| MeSH | Animals Cell Death Cell Line, Tumor Cell Survival Gene Dosage Genes, Transgenic, Suicide* Genetic Therapy* Genetic Vectors / genetics* Humans Mesenchymal Stem Cells / cytology Mesenchymal Stem Cells / metabolism* Neoplasms / genetics Neoplasms / pathology Neoplasms / therapy* Rats Retroviridae / genetics* Transduction, Genetic |
| IF | 3.258 |
| 引用数 | 86 |
| WOS 分野 | BIOTECHNOLOGY & APPLIED MICROBIOLOGY MEDICINE, RESEARCH & EXPERIMENTAL GENETICS & HEREDITY |
| リソース情報 | |
| ヒト・動物細胞 | Rat-1(RCB1830) |