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Novel Semi-Replicative Retroviral Vector Mediated Double Suicide Gene Transfer Enhances Antitumor Effects in Patient-Derived Glioblastoma Models

by Mijeong Lee 1,2,†, Yeon-Soo Kim 3,†, Kyoungmin Lee 1,2,†, Moonkyung Kang 3, Hyemi Shin 1,2, Jeong-Woo Oh 1,2, Harim Koo 1,2, Donggeon Kim 2, Yejin Kim 1,2, Doo-Sik Kong 4,*, Do-Hyun Nam 1,2,4,* and Hye Won Lee 1,5,6,*
1
Department of Health Science & Technology, Samsung Advanced Institute for Health Sciences & Technology (SAIHST), Sungkyunkwan University, Seoul 06351, Korea
2
Institute for Refractory Cancer Research, Samsung Medical Center, Seoul 06351, Korea
3
Graduate School of New Drug Discovery and Development, Chungnam National University, Daejeon 34134, Korea
4
Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06531, Korea
5
Department of Anatomy and Cell Biology, Sungkyunkwan University School of Medicine, 2066 Seobu-ro, Suwon 16149, Korea
6
Single Cell Network Research Center, Sungkyunkwan University, Suwon 16149, Korea
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Cancers 2019, 11(8), 1090; https://doi.org/10.3390/cancers11081090
Received: 11 May 2019 / Revised: 12 July 2019 / Accepted: 30 July 2019 / Published: 31 July 2019
As glioblastomas are mostly localized infiltrative lesions, gene therapy based on the retroviral replicating vector (RRV) system is considered an attractive strategy. Combinations of multiple suicide genes can circumvent the limitations associated with each gene, achieving direct and synergistic cytotoxic effects, along with bystander cell killing. In this study, we constructed a semi-and pseudotyped-RRV (sp-RRV) system harboring two suicide genes—herpes simplex virus type 1 thymidine kinase (TK) and yeast cytosine deaminase (CD)to verify the dissemination and antitumor efficacy of our sp-RRV system (spRRVe-sEF1α-TK/sRRVgp-sEF1α-CD) in seven patient-derived glioblastoma stem-like cells (GSCs). Flow cytometry and high-content analysis revealed a wide range of transduction efficiency and good correlation between the delivery of therapeutic genes and susceptibility to the prodrugs ganciclovir and 5-fluorocytosine in patient-derived GSCs in vitro. Intra-tumoral delivery of spRRVe-sEF1α-TK/sRRVgp-sEF1α-CD, combined with prodrug treatment, synergistically inhibited cell proliferation and angiogenesis while increasing apoptosis and the depletion of tumor-associated macrophages in orthotopic glioblastoma xenografts. Genomic profiling of patient-derived GSCs revealed that the key genes preventing sp-RRV infection and transmission were associated with cell adhesion, migration, development, differentiation, and proliferation. This is the first report demonstrating that a novel sp-RRV-mediated TK/CD double suicide gene transfer system has high oncolytic power against extremely heterogeneous and treatment-refractory glioblastomas. View Full-Text
Keywords: glioblastoma; patient-derived glioblastoma stem-like cells; semi- and pseudotyped-retroviral replicating vector; dual suicide gene therapy; bystander effect glioblastoma; patient-derived glioblastoma stem-like cells; semi- and pseudotyped-retroviral replicating vector; dual suicide gene therapy; bystander effect
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MDPI and ACS Style

Lee, M.; Kim, Y.-S.; Lee, K.; Kang, M.; Shin, H.; Oh, J.-W.; Koo, H.; Kim, D.; Kim, Y.; Kong, D.-S.; Nam, D.-H.; Lee, H.W. Novel Semi-Replicative Retroviral Vector Mediated Double Suicide Gene Transfer Enhances Antitumor Effects in Patient-Derived Glioblastoma Models. Cancers 2019, 11, 1090.

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