Effects of intravenously administered recombinant vesicular stomatitis virus (VSV(deltaM51)) on multifocal and invasive gliomas.
BACKGROUND
An ideal virus for the treatment of cancer should have effective delivery into multiple sites within the tumor, evade immune responses, produce rapid viral replication, spread within the tumor, and infect multiple tumors. Vesicular stomatitis virus (VSV) has been shown to be an effective oncolytic virus in a variety of tumor models, and mutations in the matrix (M) protein enhance VSV's effectiveness in animal models.


METHODS
We evaluated the susceptibility of 14 glioma cell lines to infection and killing by mutant strain VSV(deltaM51), which contains a single-amino acid deletion in the M protein. We also examined the activity and safety of this strain against the U87 and U118 experimental models of human malignant glioma in nude mice and analyzed the distribution of the virus in the brains of U87 tumor-bearing mice using fluorescence labeling. Finally, we examined the effect of VSV(deltaM51) on 15 primary human gliomas cultured from surgical specimens. All statistical tests were two-sided.


RESULTS
All 14 glioma cell lines were susceptible to VSV(deltaM51) infection and killing. Intratumoral administration of VSV(deltaM51) produced marked regression of malignant gliomas in nude mice. When administered systemically, live VSV(deltaM51) virus, as compared with dead virus, statistically significantly prolonged survival of mice with unilateral U87 tumors (median survival: 113 versus 46 days, P = .0001) and bilateral U87 tumors (median survival: 73 versus 46 days, P = .0025). VSV(deltaM51) infected multifocal gliomas, invasive glioma cells that migrated beyond the main glioma, and all 15 primary human gliomas. There was no evidence of toxicity.


CONCLUSIONS
Systemically delivered VSV(deltaM51) was an effective and safe oncolytic agent against laboratory models of multifocal and invasive malignant gliomas, the most challenging clinical manifestations of this disease.
Lun
XueQing
X
Department of Oncology, Tom Baker Cancer Centre, University of Calgary, Calgary, AB, Canada.
Senger
Donna L
DL
Alain
Tommy
T
Oprea
Andra
A
Parato
Kelley
K
Stojdl
Dave
D
Lichty
Brian
B
Power
Anthony
A
Johnston
Randal N
RN
Hamilton
Mark
M
Parney
Ian
I
Bell
John C
JC
Forsyth
Peter A
PA
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000188:drug therapy / Q000473:pathology* / Q000628:therapy*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005456:Fluorescent Dyes; D015972:Gene Expression Regulation, Neoplastic; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005910:Glioma / Q000188:drug therapy / Q000473:pathology* / Q000628:therapy*; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007275:Injections, Intravenous; D008164:Luminescent Proteins; D051379:Mice; D008819:Mice, Nude; D050130:Oncolytic Virotherapy / Q000379:methods*; D011994:Recombinant Proteins / Q000008:administration & dosage; D012107:Research Design; D018353:Rhabdoviridae Infections / Q000821:virology; D014162:Transfection; D014407:Tumor Cells, Cultured; D014763:Viral Matrix Proteins / Q000008:administration & dosage* / Q000235:genetics; D000097573:Red Fluorescent Protein
D000970:Antineoplastic Agents; D005456:Fluorescent Dyes; D005904:Glial Fibrillary Acidic Protein; D008164:Luminescent Proteins; D011994:Recombinant Proteins; D014763:Viral Matrix Proteins; D000097573:Red Fluorescent Protein; C094460:M protein, Vesicular stomatitis virus