Recombinant vesicular stomatitis virus vectors as oncolytic agents in the treatment of high-grade gliomas in an organotypic brain tissue slice-glioma coculture model

Christopher D. Duntsch, Qihong Zhou, Himangi R. Jayakar, James D. Weimar, Jon H. Robertson, Lawrence Pfeffer, Lie Wang, Zixiu Xiang, Michael Whitt

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Object. The purpose of this study was to evaluate both replication-competent and replication-restricted recombinant vesicular stomatitis virus (VSV) vectors as therapeutic agents for high-grade gliomas by using an organotypic brain tissue slice-glioma coculture system. Methods. The coculture system involved growing different brain structures together to allow neurons from these tissues to develop synaptic connections similar to those found in vivo. Rat C6 or human U87 glioma cells were then introduced into the culture to evaluate VSV as an oncolytic therapy. The authors found that recombinant wild-type VSV (rVSV-wt) rapidly eliminated C6 glioma cells from the coculture, but also caused significant damage to neurons, as measured by a loss of microtubule-associated protein 2 immunoreactivity and a failure in electrophysiological responses from neurons in the tissue slice. Nonetheless, pretreatment with interferon beta (IFNβ) virtually eliminated VSV infection in healthy tissues without impeding any oncolytic effects on tumor cells. Despite the protective effects of the IFNβ pretreatment, the tissue slices still showed signs of cytopathology when exposed to rVSV-wt. In contrast, pre-treatment with IFNβ and inoculation with a replication-restricted vector with its glycoprotein gene deleted (rVSV-AG) effectively destroyed rat C6 and human U87 glioma cells in the coculture, without causing detectable damage to the neuronal integrity and electrophysiological properties of the healthy tissue in the culture. Conclusions. Data in this study provide in vitro proof-of-principle that rVSV-AG is an effective oncolytic agent that has minimal toxic side effects to neurons compared with rVSV-wt and therefore should be considered for development as an adjuvant to surgery in the treatment of glioma.

Original languageEnglish (US)
Pages (from-to)1049-1059
Number of pages11
JournalJournal of Neurosurgery
Volume100
Issue number6
DOIs
StatePublished - Jan 1 2004

Fingerprint

Vesicular Stomatitis
Coculture Techniques
Glioma
Viruses
Interferon-beta
Brain
Neurons
Oncolytic Virotherapy
Therapeutics
Microtubule-Associated Proteins
Poisons
Virus Diseases
Glycoproteins
Genes
Neoplasms

All Science Journal Classification (ASJC) codes

  • Surgery
  • Clinical Neurology

Cite this

Recombinant vesicular stomatitis virus vectors as oncolytic agents in the treatment of high-grade gliomas in an organotypic brain tissue slice-glioma coculture model. / Duntsch, Christopher D.; Zhou, Qihong; Jayakar, Himangi R.; Weimar, James D.; Robertson, Jon H.; Pfeffer, Lawrence; Wang, Lie; Xiang, Zixiu; Whitt, Michael.

In: Journal of Neurosurgery, Vol. 100, No. 6, 01.01.2004, p. 1049-1059.

Research output: Contribution to journalArticle

Duntsch, Christopher D. ; Zhou, Qihong ; Jayakar, Himangi R. ; Weimar, James D. ; Robertson, Jon H. ; Pfeffer, Lawrence ; Wang, Lie ; Xiang, Zixiu ; Whitt, Michael. / Recombinant vesicular stomatitis virus vectors as oncolytic agents in the treatment of high-grade gliomas in an organotypic brain tissue slice-glioma coculture model. In: Journal of Neurosurgery. 2004 ; Vol. 100, No. 6. pp. 1049-1059.
@article{d3b465c9b15c433ebbf4a8de45bffad3,
title = "Recombinant vesicular stomatitis virus vectors as oncolytic agents in the treatment of high-grade gliomas in an organotypic brain tissue slice-glioma coculture model",
abstract = "Object. The purpose of this study was to evaluate both replication-competent and replication-restricted recombinant vesicular stomatitis virus (VSV) vectors as therapeutic agents for high-grade gliomas by using an organotypic brain tissue slice-glioma coculture system. Methods. The coculture system involved growing different brain structures together to allow neurons from these tissues to develop synaptic connections similar to those found in vivo. Rat C6 or human U87 glioma cells were then introduced into the culture to evaluate VSV as an oncolytic therapy. The authors found that recombinant wild-type VSV (rVSV-wt) rapidly eliminated C6 glioma cells from the coculture, but also caused significant damage to neurons, as measured by a loss of microtubule-associated protein 2 immunoreactivity and a failure in electrophysiological responses from neurons in the tissue slice. Nonetheless, pretreatment with interferon beta (IFNβ) virtually eliminated VSV infection in healthy tissues without impeding any oncolytic effects on tumor cells. Despite the protective effects of the IFNβ pretreatment, the tissue slices still showed signs of cytopathology when exposed to rVSV-wt. In contrast, pre-treatment with IFNβ and inoculation with a replication-restricted vector with its glycoprotein gene deleted (rVSV-AG) effectively destroyed rat C6 and human U87 glioma cells in the coculture, without causing detectable damage to the neuronal integrity and electrophysiological properties of the healthy tissue in the culture. Conclusions. Data in this study provide in vitro proof-of-principle that rVSV-AG is an effective oncolytic agent that has minimal toxic side effects to neurons compared with rVSV-wt and therefore should be considered for development as an adjuvant to surgery in the treatment of glioma.",
author = "Duntsch, {Christopher D.} and Qihong Zhou and Jayakar, {Himangi R.} and Weimar, {James D.} and Robertson, {Jon H.} and Lawrence Pfeffer and Lie Wang and Zixiu Xiang and Michael Whitt",
year = "2004",
month = "1",
day = "1",
doi = "10.3171/jns.2004.100.6.1049",
language = "English (US)",
volume = "100",
pages = "1049--1059",
journal = "Journal of Neurosurgery",
issn = "0022-3085",
publisher = "American Association of Neurological Surgeons",
number = "6",

}

TY - JOUR

T1 - Recombinant vesicular stomatitis virus vectors as oncolytic agents in the treatment of high-grade gliomas in an organotypic brain tissue slice-glioma coculture model

AU - Duntsch, Christopher D.

AU - Zhou, Qihong

AU - Jayakar, Himangi R.

AU - Weimar, James D.

AU - Robertson, Jon H.

AU - Pfeffer, Lawrence

AU - Wang, Lie

AU - Xiang, Zixiu

AU - Whitt, Michael

PY - 2004/1/1

Y1 - 2004/1/1

N2 - Object. The purpose of this study was to evaluate both replication-competent and replication-restricted recombinant vesicular stomatitis virus (VSV) vectors as therapeutic agents for high-grade gliomas by using an organotypic brain tissue slice-glioma coculture system. Methods. The coculture system involved growing different brain structures together to allow neurons from these tissues to develop synaptic connections similar to those found in vivo. Rat C6 or human U87 glioma cells were then introduced into the culture to evaluate VSV as an oncolytic therapy. The authors found that recombinant wild-type VSV (rVSV-wt) rapidly eliminated C6 glioma cells from the coculture, but also caused significant damage to neurons, as measured by a loss of microtubule-associated protein 2 immunoreactivity and a failure in electrophysiological responses from neurons in the tissue slice. Nonetheless, pretreatment with interferon beta (IFNβ) virtually eliminated VSV infection in healthy tissues without impeding any oncolytic effects on tumor cells. Despite the protective effects of the IFNβ pretreatment, the tissue slices still showed signs of cytopathology when exposed to rVSV-wt. In contrast, pre-treatment with IFNβ and inoculation with a replication-restricted vector with its glycoprotein gene deleted (rVSV-AG) effectively destroyed rat C6 and human U87 glioma cells in the coculture, without causing detectable damage to the neuronal integrity and electrophysiological properties of the healthy tissue in the culture. Conclusions. Data in this study provide in vitro proof-of-principle that rVSV-AG is an effective oncolytic agent that has minimal toxic side effects to neurons compared with rVSV-wt and therefore should be considered for development as an adjuvant to surgery in the treatment of glioma.

AB - Object. The purpose of this study was to evaluate both replication-competent and replication-restricted recombinant vesicular stomatitis virus (VSV) vectors as therapeutic agents for high-grade gliomas by using an organotypic brain tissue slice-glioma coculture system. Methods. The coculture system involved growing different brain structures together to allow neurons from these tissues to develop synaptic connections similar to those found in vivo. Rat C6 or human U87 glioma cells were then introduced into the culture to evaluate VSV as an oncolytic therapy. The authors found that recombinant wild-type VSV (rVSV-wt) rapidly eliminated C6 glioma cells from the coculture, but also caused significant damage to neurons, as measured by a loss of microtubule-associated protein 2 immunoreactivity and a failure in electrophysiological responses from neurons in the tissue slice. Nonetheless, pretreatment with interferon beta (IFNβ) virtually eliminated VSV infection in healthy tissues without impeding any oncolytic effects on tumor cells. Despite the protective effects of the IFNβ pretreatment, the tissue slices still showed signs of cytopathology when exposed to rVSV-wt. In contrast, pre-treatment with IFNβ and inoculation with a replication-restricted vector with its glycoprotein gene deleted (rVSV-AG) effectively destroyed rat C6 and human U87 glioma cells in the coculture, without causing detectable damage to the neuronal integrity and electrophysiological properties of the healthy tissue in the culture. Conclusions. Data in this study provide in vitro proof-of-principle that rVSV-AG is an effective oncolytic agent that has minimal toxic side effects to neurons compared with rVSV-wt and therefore should be considered for development as an adjuvant to surgery in the treatment of glioma.

UR - http://www.scopus.com/inward/record.url?scp=2442712715&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=2442712715&partnerID=8YFLogxK

U2 - 10.3171/jns.2004.100.6.1049

DO - 10.3171/jns.2004.100.6.1049

M3 - Article

VL - 100

SP - 1049

EP - 1059

JO - Journal of Neurosurgery

JF - Journal of Neurosurgery

SN - 0022-3085

IS - 6

ER -