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    Please use this identifier to cite or link to this item: https://ir.cnu.edu.tw/handle/310902800/34143

    標題: Efficient Prodrug Activator Gene Therapy by Retroviral Replicating Vectors Prolongs Survival in an Immune-Competent Intracerebral Glioma Model
    作者: Chen, Shih-Han
    Sun, Jui-Ming
    Chen, Bing-Mao
    Lin, Sheng-Che
    Chang, Hao-Fang
    Collins, Sara
    Chang, Deching
    Wu, Shu-Fen
    Lu, Yin-Che
    Wang, Weijun
    Chen, Thomas C.
    Kasahara, Noriyuki
    Wang, Hsin-Ell
    Tai, Chien-Kuo
    貢獻者: Ditmanson Med Fdn, Dept Surg, Sect Neurosurg, Chia Yi Christian Hosp
    Asia Univ, Dept Biotechnol
    Natl Chung Cheng Univ, Dept Biomed Sci
    Univ Calif San Francisco, Dept Neurol Surg, San Francisco
    Chia Nan Univ Pharm & Sci, Dept Hlth & Nutr
    Univ Southern Calif, Dept Neurosurg, Los Angeles
    Univ Calif San Francisco, Dept Radiat Oncol, San Francisco
    Natl Yang Ming Univ, Dept Biomed Imaging & Radiol Sci
    關鍵字: brain tumor
    retroviral replicating vector
    prodrug activator
    gene therapy
    E. coli nitroreductase gene
    日期: 2020
    上傳時間: 2022-11-18 11:25:48 (UTC+8)
    出版者: Mdpi
    摘要: 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 E. coli 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.
    關聯: International Journal of Molecular Sciences, v.21, n.4, pp.12
    Appears in Collections:[保健營養系(所) ] 期刊論文

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