Efficient Prodrug Activator Gene Therapy by Retroviral Replicating Vectors Prolongs Survival in an Immune-Competent Intracerebral Glioma Model
Prodrug activator gene therapy mediated by murine leukemia virus (MLV)-based retroviral replicating vectors (RRV) was previously shown to be highly effective in killing glioma cells both in culture and in vivo. To avoid receptor interference and enable dual vector co-infection with MLV-RRV, we have...
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doaj-6cc1ed56576f4fada7e8f73cb9a1072d2020-11-25T03:02:16ZengMDPI AGInternational Journal of Molecular Sciences1422-00672020-02-01214143310.3390/ijms21041433ijms21041433Efficient Prodrug Activator Gene Therapy by Retroviral Replicating Vectors Prolongs Survival in an Immune-Competent Intracerebral Glioma ModelShih-Han Chen0Jui-Ming Sun1Bing-Mao Chen2Sheng-Che Lin3Hao-Fang Chang4Sara Collins5Deching Chang6Shu-Fen Wu7Yin-Che Lu8Weijun Wang9Thomas C. Chen10Noriyuki Kasahara11Hsin-Ell Wang12Chien-Kuo Tai13Section of Neurosurgery, Department of Surgery, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chia-Yi 600, TaiwanSection of Neurosurgery, Department of Surgery, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chia-Yi 600, TaiwanDepartment of Biomedical Sciences, National Chung Cheng University, Chia-Yi 621, TaiwanDepartment of Biomedical Sciences, National Chung Cheng University, Chia-Yi 621, TaiwanDepartment of Biomedical Sciences, National Chung Cheng University, Chia-Yi 621, TaiwanDepartment of Neurological Surgery, University of California, San Francisco, CA 94143, USADepartment of Biomedical Sciences, National Chung Cheng University, Chia-Yi 621, TaiwanDepartment of Biomedical Sciences, National Chung Cheng University, Chia-Yi 621, TaiwanDepartment of Health and Nutrition, Chia Nan University of Pharmacy and Science, Tainan 717, TaiwanDepartment of Neurosurgery, University of Southern California, Los Angeles, CA 90033, USADepartment of Neurosurgery, University of Southern California, Los Angeles, CA 90033, USADepartment of Neurological Surgery, University of California, San Francisco, CA 94143, USADepartment of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei 112, TaiwanDepartment of Biomedical Sciences, National Chung Cheng University, Chia-Yi 621, TaiwanProdrug activator gene therapy mediated by murine leukemia virus (MLV)-based retroviral replicating vectors (RRV) was previously shown to be highly effective in killing glioma cells both in culture and in vivo. To avoid receptor interference and enable dual vector co-infection with MLV-RRV, we have developed another RRV based on gibbon ape leukemia virus (GALV) that also shows robust replicative spread in a wide variety of tumor cells. We evaluated the potential of GALV-based RRV as a cancer therapeutic agent by incorporating yeast cytosine deaminase (CD) and <i>E. coli</i> nitroreductase (NTR) prodrug activator genes into the vector. The expression of CD and NTR genes from GALV-RRV achieved highly efficient delivery of these prodrug activator genes to RG-2 glioma cells, resulting in enhanced cytotoxicity after administering their respective prodrugs 5-fluorocytosine and CB1954 in vitro. In an immune-competent intracerebral RG-2 glioma model, GALV-mediated CD and NTR gene therapy both significantly suppressed tumor growth with CB1954 administration after a single injection of vector supernatant. However, NTR showed greater potency than CD, with control animals receiving GALV-NTR vector alone (i.e., without CB1954 prodrug) showing extensive tumor growth with a median survival time of 17.5 days, while animals receiving GALV-NTR and CB1954 showed significantly prolonged survival with a median survival time of 30 days. In conclusion, GALV-RRV enabled high-efficiency gene transfer and persistent expression of NTR, resulting in efficient cell killing, suppression of tumor growth, and prolonged survival upon CB1954 administration. This validates the use of therapeutic strategies employing this prodrug activator gene to arm GALV-RRV, and opens the door to the possibility of future combination gene therapy with CD-armed MLV-RRV, as the latter vector is currently being evaluated in clinical trials.https://www.mdpi.com/1422-0067/21/4/1433brain tumorretroviral replicating vectorprodrug activatorgene therapy<i>e. coli</i> nitroreductase gene |
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language |
English |
format |
Article |
sources |
DOAJ |
author |
Shih-Han Chen Jui-Ming Sun Bing-Mao Chen Sheng-Che Lin Hao-Fang Chang Sara Collins Deching Chang Shu-Fen Wu Yin-Che Lu Weijun Wang Thomas C. Chen Noriyuki Kasahara Hsin-Ell Wang Chien-Kuo Tai |
spellingShingle |
Shih-Han Chen Jui-Ming Sun Bing-Mao Chen Sheng-Che Lin Hao-Fang Chang Sara Collins Deching Chang Shu-Fen Wu Yin-Che Lu Weijun Wang Thomas C. Chen Noriyuki Kasahara Hsin-Ell Wang Chien-Kuo Tai Efficient Prodrug Activator Gene Therapy by Retroviral Replicating Vectors Prolongs Survival in an Immune-Competent Intracerebral Glioma Model International Journal of Molecular Sciences brain tumor retroviral replicating vector prodrug activator gene therapy <i>e. coli</i> nitroreductase gene |
author_facet |
Shih-Han Chen Jui-Ming Sun Bing-Mao Chen Sheng-Che Lin Hao-Fang Chang Sara Collins Deching Chang Shu-Fen Wu Yin-Che Lu Weijun Wang Thomas C. Chen Noriyuki Kasahara Hsin-Ell Wang Chien-Kuo Tai |
author_sort |
Shih-Han Chen |
title |
Efficient Prodrug Activator Gene Therapy by Retroviral Replicating Vectors Prolongs Survival in an Immune-Competent Intracerebral Glioma Model |
title_short |
Efficient Prodrug Activator Gene Therapy by Retroviral Replicating Vectors Prolongs Survival in an Immune-Competent Intracerebral Glioma Model |
title_full |
Efficient Prodrug Activator Gene Therapy by Retroviral Replicating Vectors Prolongs Survival in an Immune-Competent Intracerebral Glioma Model |
title_fullStr |
Efficient Prodrug Activator Gene Therapy by Retroviral Replicating Vectors Prolongs Survival in an Immune-Competent Intracerebral Glioma Model |
title_full_unstemmed |
Efficient Prodrug Activator Gene Therapy by Retroviral Replicating Vectors Prolongs Survival in an Immune-Competent Intracerebral Glioma Model |
title_sort |
efficient prodrug activator gene therapy by retroviral replicating vectors prolongs survival in an immune-competent intracerebral glioma model |
publisher |
MDPI AG |
series |
International Journal of Molecular Sciences |
issn |
1422-0067 |
publishDate |
2020-02-01 |
description |
Prodrug activator gene therapy mediated by murine leukemia virus (MLV)-based retroviral replicating vectors (RRV) was previously shown to be highly effective in killing glioma cells both in culture and in vivo. To avoid receptor interference and enable dual vector co-infection with MLV-RRV, we have developed another RRV based on gibbon ape leukemia virus (GALV) that also shows robust replicative spread in a wide variety of tumor cells. We evaluated the potential of GALV-based RRV as a cancer therapeutic agent by incorporating yeast cytosine deaminase (CD) and <i>E. coli</i> nitroreductase (NTR) prodrug activator genes into the vector. The expression of CD and NTR genes from GALV-RRV achieved highly efficient delivery of these prodrug activator genes to RG-2 glioma cells, resulting in enhanced cytotoxicity after administering their respective prodrugs 5-fluorocytosine and CB1954 in vitro. In an immune-competent intracerebral RG-2 glioma model, GALV-mediated CD and NTR gene therapy both significantly suppressed tumor growth with CB1954 administration after a single injection of vector supernatant. However, NTR showed greater potency than CD, with control animals receiving GALV-NTR vector alone (i.e., without CB1954 prodrug) showing extensive tumor growth with a median survival time of 17.5 days, while animals receiving GALV-NTR and CB1954 showed significantly prolonged survival with a median survival time of 30 days. In conclusion, GALV-RRV enabled high-efficiency gene transfer and persistent expression of NTR, resulting in efficient cell killing, suppression of tumor growth, and prolonged survival upon CB1954 administration. This validates the use of therapeutic strategies employing this prodrug activator gene to arm GALV-RRV, and opens the door to the possibility of future combination gene therapy with CD-armed MLV-RRV, as the latter vector is currently being evaluated in clinical trials. |
topic |
brain tumor retroviral replicating vector prodrug activator gene therapy <i>e. coli</i> nitroreductase gene |
url |
https://www.mdpi.com/1422-0067/21/4/1433 |
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