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VOL. 76 (3), 327-342, 2010 ANTITUMORAL ACTIVITY OF ONCOLYTIC VACCINIA VIRUS...

1. INTRODUCTION

Cancer is a multi-faceted process by which cells are sequentially
transformed, lose cell growth control, develop tumours at specific
sites and cells spread to different tissues leading to metastasis.
Different strategies to fight cancer are used in the clinic, from sur-
gery to chemotherapy, immune-therapy and more recently, although
experimentally, through the use of viral vectors with the ability to de-
stroy tumour cells. This therapeutic strategy uses oncolytic viral vec-
tors with preference for replication in tumour cells, causing cell de-
struction (1). Vaccinia virus has a strong oncolytic effect due to its
fast replication cycle and a high innate tropism to cancer tissue (2).
Tumour targeting can be further improved by deleting vaccinia virus
genes that are necessary for replication in normal cells but not in can-
cer cells. For example, deletions of either thymidine kinase (TK), vac-
cinia virus growth factor (VGF), or both have been shown to reduce
pathogenicity compared to wild-type virus (3, 4). To enhance antitu-
mor potency, oncolytic vaccinia viruses can be armed with therapeu-
tic transgenes, such as immunostimulatory factors or suicide genes.
The clinical data obtained thus far with the oncolytic poxvirus vec-
tors shows that intratumoral injection and replication lead to repro-
ducible delivery of the virus to systemic metastasis through the blood-
stream with tumour necrosis; however, hurdles remain. Neutralizing
response to the virus vector, nature of the inflammatory response re-
quired for tumour regression and limited application to locally ad-
vanced tumours, are among obstacles to be solved. Thus, develop-
ment of poxvirus vectors with improved oncolytic characteristics are
needed.

To search for novel viral vectors with enhanced oncolytic activity,
we have taken advantage of a property of cancer cells, which frequent-
ly lose their ability to produce or respond to interferons (IFN). These
molecules play critical roles in host defence against viral infections,
control of cell growth and immune modulation (5). The poor response
of tumour cells to IFN make these cells more prone to viral infection,
hence forming the basis by which oncolytic viruses are used to de-
stroy tumour cells as they replicate to a better extent in tumour cells
than in normal cells. Among the proteins induced by IFN with antivi-
ral importance is the ds-RNA dependent protein kinase PKR, an en-

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