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

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

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 cyt...

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Main Authors: Mijeong Lee, Yeon-Soo Kim, Kyoungmin Lee, Moonkyung Kang, Hyemi Shin, Jeong-Woo Oh, Harim Koo, Donggeon Kim, Yejin Kim, Doo-Sik Kong, Do-Hyun Nam, Hye Won Lee
Format: Article
Language:English
Published: MDPI AG 2019-07-01
Series:Cancers
Subjects:
glioblastoma
patient-derived glioblastoma stem-like cells
semi- and pseudotyped-retroviral replicating vector
dual suicide gene therapy
bystander effect
Online Access:https://www.mdpi.com/2072-6694/11/8/1090
id doaj-3c068320e3554e65aab26427319b83d1
record_format Article
collection DOAJ
language English
format Article
sources DOAJ
author Mijeong Lee
Yeon-Soo Kim
Kyoungmin Lee
Moonkyung Kang
Hyemi Shin
Jeong-Woo Oh
Harim Koo
Donggeon Kim
Yejin Kim
Doo-Sik Kong
Do-Hyun Nam
Hye Won Lee
spellingShingle Mijeong Lee
Yeon-Soo Kim
Kyoungmin Lee
Moonkyung Kang
Hyemi Shin
Jeong-Woo Oh
Harim Koo
Donggeon Kim
Yejin Kim
Doo-Sik Kong
Do-Hyun Nam
Hye Won Lee
Novel Semi-Replicative Retroviral Vector Mediated Double Suicide Gene Transfer Enhances Antitumor Effects in Patient-Derived Glioblastoma Models
Cancers
glioblastoma
patient-derived glioblastoma stem-like cells
semi- and pseudotyped-retroviral replicating vector
dual suicide gene therapy
bystander effect
author_facet Mijeong Lee
Yeon-Soo Kim
Kyoungmin Lee
Moonkyung Kang
Hyemi Shin
Jeong-Woo Oh
Harim Koo
Donggeon Kim
Yejin Kim
Doo-Sik Kong
Do-Hyun Nam
Hye Won Lee
author_sort Mijeong Lee
title Novel Semi-Replicative Retroviral Vector Mediated Double Suicide Gene Transfer Enhances Antitumor Effects in Patient-Derived Glioblastoma Models
title_short Novel Semi-Replicative Retroviral Vector Mediated Double Suicide Gene Transfer Enhances Antitumor Effects in Patient-Derived Glioblastoma Models
title_full Novel Semi-Replicative Retroviral Vector Mediated Double Suicide Gene Transfer Enhances Antitumor Effects in Patient-Derived Glioblastoma Models
title_fullStr Novel Semi-Replicative Retroviral Vector Mediated Double Suicide Gene Transfer Enhances Antitumor Effects in Patient-Derived Glioblastoma Models
title_full_unstemmed Novel Semi-Replicative Retroviral Vector Mediated Double Suicide Gene Transfer Enhances Antitumor Effects in Patient-Derived Glioblastoma Models
title_sort novel semi-replicative retroviral vector mediated double suicide gene transfer enhances antitumor effects in patient-derived glioblastoma models
publisher MDPI AG
series Cancers
issn 2072-6694
publishDate 2019-07-01
description 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&#8212;herpes simplex virus type 1 thymidine kinase (<i>TK</i>) and yeast cytosine deaminase (<i>CD</i>)<i>&#8212;</i>to verify the dissemination and antitumor efficacy of our sp-RRV system (spRRVe-sEF1&#945;-<i>TK</i>/sRRVgp-sEF1&#945;-<i>CD</i>) 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-sEF1&#945;-<i>TK</i>/sRRVgp-sEF1&#945;-<i>CD</i>, 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 <i>TK</i>/<i>CD</i> double suicide gene transfer system has high oncolytic power against extremely heterogeneous and treatment-refractory glioblastomas.
topic glioblastoma
patient-derived glioblastoma stem-like cells
semi- and pseudotyped-retroviral replicating vector
dual suicide gene therapy
bystander effect
url https://www.mdpi.com/2072-6694/11/8/1090
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spelling doaj-3c068320e3554e65aab26427319b83d12020-11-25T01:17:07ZengMDPI AGCancers2072-66942019-07-01118109010.3390/cancers11081090cancers11081090Novel Semi-Replicative Retroviral Vector Mediated Double Suicide Gene Transfer Enhances Antitumor Effects in Patient-Derived Glioblastoma ModelsMijeong Lee0Yeon-Soo Kim1Kyoungmin Lee2Moonkyung Kang3Hyemi Shin4Jeong-Woo Oh5Harim Koo6Donggeon Kim7Yejin Kim8Doo-Sik Kong9Do-Hyun Nam10Hye Won Lee11Department of Health Science &amp; Technology, Samsung Advanced Institute for Health Sciences &amp; Technology (SAIHST), Sungkyunkwan University, Seoul 06351, KoreaGraduate School of New Drug Discovery and Development, Chungnam National University, Daejeon 34134, KoreaDepartment of Health Science &amp; Technology, Samsung Advanced Institute for Health Sciences &amp; Technology (SAIHST), Sungkyunkwan University, Seoul 06351, KoreaGraduate School of New Drug Discovery and Development, Chungnam National University, Daejeon 34134, KoreaDepartment of Health Science &amp; Technology, Samsung Advanced Institute for Health Sciences &amp; Technology (SAIHST), Sungkyunkwan University, Seoul 06351, KoreaDepartment of Health Science &amp; Technology, Samsung Advanced Institute for Health Sciences &amp; Technology (SAIHST), Sungkyunkwan University, Seoul 06351, KoreaDepartment of Health Science &amp; Technology, Samsung Advanced Institute for Health Sciences &amp; Technology (SAIHST), Sungkyunkwan University, Seoul 06351, KoreaInstitute for Refractory Cancer Research, Samsung Medical Center, Seoul 06351, KoreaDepartment of Health Science &amp; Technology, Samsung Advanced Institute for Health Sciences &amp; Technology (SAIHST), Sungkyunkwan University, Seoul 06351, KoreaDepartment of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06531, KoreaDepartment of Health Science &amp; Technology, Samsung Advanced Institute for Health Sciences &amp; Technology (SAIHST), Sungkyunkwan University, Seoul 06351, KoreaDepartment of Health Science &amp; Technology, Samsung Advanced Institute for Health Sciences &amp; Technology (SAIHST), Sungkyunkwan University, Seoul 06351, KoreaAs 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&#8212;herpes simplex virus type 1 thymidine kinase (<i>TK</i>) and yeast cytosine deaminase (<i>CD</i>)<i>&#8212;</i>to verify the dissemination and antitumor efficacy of our sp-RRV system (spRRVe-sEF1&#945;-<i>TK</i>/sRRVgp-sEF1&#945;-<i>CD</i>) 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-sEF1&#945;-<i>TK</i>/sRRVgp-sEF1&#945;-<i>CD</i>, 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 <i>TK</i>/<i>CD</i> double suicide gene transfer system has high oncolytic power against extremely heterogeneous and treatment-refractory glioblastomas.https://www.mdpi.com/2072-6694/11/8/1090glioblastomapatient-derived glioblastoma stem-like cellssemi- and pseudotyped-retroviral replicating vectordual suicide gene therapybystander effect

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