Recombinant vesicular stomatitis virus vectors as oncolytic agents in the treatment of high-grade gliomas in an organotypic brain tissue slice-glioma coculture model.
OBJECTIVE
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 (IFNbeta) virtually eliminated VSV infection in healthy tissues without impeding any oncolytic effects on tumor cells. Despite the protective effects of the IFNbeta pretreatment, the tissue slices still showed signs of cytopathology when exposed to rVSV-wt. In contrast, pretreatment with IFNbeta and inoculation with a replication-restricted vector with its glycoprotein gene deleted (rVSV-deltaG) 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-deltaG 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.
Duntsch
Christopher D
CD
Department of Neurosurgery, The University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA. duntsch@bellsouth.net
Zhou
Qihong
Q
Jayakar
Himangi R
HR
Weimar
James D
JD
Robertson
Jon H
JH
Pfeffer
Lawrence M
LM
Wang
Lie
L
Xiang
Zixiu
Z
Whitt
Michael A
MA
D000818:Animals; D001932:Brain Neoplasms / Q000473:pathology / Q000628:therapy*; D046508:Culture Techniques; D004594:Electrophysiology; D005910:Glioma / Q000473:pathology / Q000628:therapy*; D006801:Humans; D016899:Interferon-beta / Q000494:pharmacology; D009474:Neurons; D051381:Rats; D013569:Synapses; D014407:Tumor Cells, Cultured; D014721:Vesicular stomatitis Indiana virus / Q000235:genetics* / Q000472:pathogenicity*
D016899:Interferon-beta