Efficacy of systemically administered mutant vesicular stomatitis virus (VSVDelta51) combined with radiation for nasopharyngeal carcinoma.
OBJECTIVE
Nasopharyngeal carcinoma (NPC) is a malignancy of the head and neck region that is associated with EBV latency. Curative treatments for NPC achieve modest survival rates, underscoring a need to develop novel therapies. We evaluated the therapeutic potential of a mutant vesicular stomatitis virus (VSVDelta51) as single treatment modality or in combination with ionizing radiation (RT) in NPC.


METHODS
MTS assay was used to assess cell viability in vitro; apoptosis was measured using propidium iodide staining and caspase activation. In vivo experiments were conducted using tumor-bearing nude mice with or without local RT (4 Gy). Apoptosis was assessed in excised tumor sections with terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining.


RESULTS
Our data showed that NPC cells are exquisitely sensitive to VSVDelta51 oncolysis, which correlated with the presence of EBV. Efficacy of VSVDelta51 against NPC cells was further augmented when combined with RT. A single systemic injection of VSVDelta51 achieved 50% survival in treated mice, which increased to 83% when combined with local tumor RT. In addition to induction of apoptosis, an antiangiogenic effect of VSVDelta51 was observed in vivo, suggesting a novel tumoricidal mechanism for VSVDelta51. This virus also prevented growth of NPC sphere-forming cells in vitro, showing potential utility in targeting NPC-initiating cells.


CONCLUSIONS
Our data represent the first report showing that EBV-positive NPC cells are exquisitely sensitive to VSVDelta51 oncolysis and documenting the successful utilization of this combinatorial regimen as a novel curative therapeutic strategy for NPC.
Alajez
Nehad M
NM
Division of Applied Molecular Oncology, Ontario Cancer Institute, Toronto, Ontario, Canada.
Mocanu
Joseph D
JD
Shi
Wei
W
Chia
Marie C
MC
Breitbach
Caroline J
CJ
Hui
Angela B Y
AB
Knowles
Shane
S
Bell
John C
JC
Busson
Pierre
P
Takada
Kenzo
K
Lo
Kwok-Wai
KW
O'Sullivan
Brian
B
Gullane
Pat
P
Liu
Fei-Fei
FF
D000818:Animals; D017209:Apoptosis; D002277:Carcinoma / Q000532:radiotherapy / Q000628:therapy*; D045744:Cell Line, Tumor; D002470:Cell Survival; D003131:Combined Modality Therapy / Q000379:methods; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D009303:Nasopharyngeal Neoplasms / Q000532:radiotherapy / Q000628:therapy*; D009368:Neoplasm Transplantation; D016896:Treatment Outcome; D018116:Vesiculovirus / Q000235:genetics / Q000378:metabolism*