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Treatment
> Gene
Therapy
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Cancer Research 65, 2832-2839, April 1, 2005
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Abstract |
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An Oncolytic HSV-1 Mutant Expressing
ICP34.5 under Control of a Nestin Promoter Increases Survival of
Animals even when Symptomatic from a Brain Tumor
Hirokazu Kambara1,
Hideyuki Okano2,3,
E. Antonio Chiocca1 and Yoshinaga Saeki1
1Dardinger Center for
Neuro-oncology, Department of Neurological Surgery, The Ohio State
University Comprehensive Cancer Center, Columbus, Ohio; 2Department
of Physiology, Keio University School of Medicine, Shinjuku-ku, Tokyo,
Japan; and 3Core Research for Evolutional Science and
Technology, Japan Science and Technology Agency, Kawaguchi, Saitama,
Japan -- Requests for reprints: E. Antonio Chiocca or Yoshinaga Saeki,
Dardinger Center for Neuro-oncology, Department of Neurological
Surgery, The Ohio State University Medical Center Comprehensive Cancer
Center, James Cancer Hospital and Solove Research Institute, N-1017
Doan Hall, 410 West 10th Avenue, Columbus, OH 43210. Phone:
614-293-9312; Fax: 614-293-4281; E-mail: Chiocca-1@medctr.osu.edu
or saeki-1@medctr.osu.edu.
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Oncolytic herpes simplex virus-1 (HSV-1)
mutants possessing mutations in the ICP34.5 and ICP6
genes have proven safe through clinical trials.
However, ICP34.5-null viruses may grow poorly in
cells due to their inability to prevent host-cell shut-off of
protein synthesis caused by hyperphosphorylation of eukaryotic initiation
factor 2α.
To increase tumor selectivity, glioma-selective expression
of ICP34.5 in the context of oncolysis may be useful.
Malignant gliomas remain an incurable disease.
One molecular marker of malignant gliomas is expression of
the intermediate filament nestin.
Expression of nestin mRNA was confirmed in 6 of 6 human
glioma lines and in 3 of 4 primary glioma cells.
Normal human astrocytes were negative.
A novel glioma-selective HSV-1 mutant (rQNestin34.5) was
thus engineered by expressing ICP34.5 under control of a
synthetic nestin promoter.
Replication, cellular propagation, and cytotoxicity of
rQNestin34.5 were significantly enhanced in cultured and
primary human glioma cell lines compared with control
virus.
However, replication, cellular propagation, and
cytotoxicity of rQNestin34.5 in normal human astrocytes
remained quantitatively similar to that of control
virus.
In glioma cell lines infected with rQNestin34.5, the level
of phospho-eukaryotic initiation factor 2α was lower than
that of cells infected by control rHsvQ1, confirming selective ICP34.5
expression in glioma cells.
In vivo, rQNestin34.5 showed significantly more
potent inhibition of tumor growth compared with control
virus.
Treatment in the brain tumor model was instituted on
animal's display of neurologic symptoms, which usually led to
rapid demise. rQNestin34.5 treatment doubled the life span of
these animals.
These results show that rQNestin34.5 could be a potent
agent for the treatment of malignant glioma.
Key Words:
Viral therapy; oncolytic viruses; glioma; gene therapy; experimental
therapy
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© 2005 American Association for Cancer Research
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