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Cyclophosphamide Allows for In vivo
Dose Reduction of a Potent Oncolytic Virus
Hirokazu Kambara, Yoshinaga
Saeki and E. Antonio Chiocca
Dardinger Center for Neuro-oncology
and Neurosciences, Department of Neurological Surgery, The Ohio State
University Comprehensive Cancer Center, Columbus, Ohio. -- Requests
for reprints: E. Antonio Chiocca, Dardinger Center for Neuro-oncology
and Neurosciences, 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:
614-293-4024; E-mail: Chiocca-1@medctr.osu.edu.
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The success of cancer virotherapy depends
on its efficacy versus toxicity profile in human clinical
trials.
Progress towards clinical trials can be hampered by the
relatively elevated doses of oncolytic viruses administered
in animal models to achieve an anticancer effect and by the
even higher doses required in humans to approximate an
animal bioequivalent dose.
Such elevated doses of injected viral proteins may also
lead to undesirable toxicities and are also very difficult
to produce in a biotechnological setting.
We report that a relatively potent herpes simplex virus type
1 oncolytic virus (rQNestin34.5) produces 45% survivors at
a dose of 3 x 104 plaque-forming units (pfu) in a 9-day-old
mouse model of human glioma.
Unlike our previous findings with less potent oncolytic
viruses, though, the preadministration of cyclophosphamide
did not enhance this survival or affect oncolytic virus
tumor distribution and tumor volume.
However, when oncolytic virus doses were reduced (3 x 103
and 3 x 102 pfu), cyclophosphamide significantly enhanced
both animal survival and oncolytic virus tumor distribution
and also reduced tumor volumes.
These findings thus show that cyclophosphamide allows for
dose reduction of doses of a relatively potent oncolytic virus,
a finding with implications for the development of clinical trials.
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