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G glycoprotein of rabies virus provided protection in dogs and expression of foreign genes of relatively large size for engineer-
cats (Ge et al., 2011) and an NDV vector expressing the F and ing improved oncolytic viruses.
H proteins of canine distemper virus also provided protection in NDV strains suitable for anti-cancer therapy have been clas-
minks (Ge et al., 2015). These results indicate that NDV is also a sified as either lytic or non-lytic for human cells. Both lytic and
promising vaccine vector for veterinary pathogens. non-lytic strains have been investigated as potential anti-cancer
agents. One major difference between lytic and non-lytic strains
is that lytic strains can produce infectious progeny in human
NDV as an oncolytic agent cancer cells and can spread in tumour tissues; whereas, non-lytic
NDV preferentially infects and kills tumour cells while sparing strains do not produce infectious progeny and cannot spread
normal cells (Elankumaran et al., 2006). NDV can replicate up in tumour tissues. The reason being the progeny of lytic strains
to 10,000 times faster in human cancer cells than in most normal contain active F protein; whereas, the progeny of non-lytic strains
human cells. Additionally, NDV possesses strong immunostimu- contains inactive F protein. Lentogenic strains behave as non-
latory properties, which activates host anti-tumour immunity. lytic virus, whereas mesogenic and velogenic strains behave as
Owing to these properties, NDV has been applied to cancer lytic virus. Lytic strains of NDV selectively replicate in and rap-
patients with beneficial results for more than 50 years (Schir- idly kill human tumour cells. Non-lytic strains of NDV also kill
rmacher, 2016). The anti-cancer effect of NDV was first reported infected cells, but more slowly with death apparently because of
by Cassel and Garret in 1965 (Cassel and Garrett, 1965). Since the result of abnormal host cell metabolism. The NDV strains that
then many preclinical and clinical trials using NDV for cancer have been evaluated most widely for treatment of human cancer
therapy have been performed (Zamarin and Palese, 2012). Some are PV701, 73-T, MTH-68 and Ulster (Cassel and Murray, 1992;
of the clinical trials reported positive results and some did not. Ahlert et al., 1997). Strains PV701, 73-T, and MTH-68 are lytic,
NDV has been labelled as a complementary and alternative while strain Ulster is non-lytic. Because the lytic strains can cause
medicine by the National Cancer Institute in the USA. Several economic losses to poultry industry, they are not allowed for viro-
approaches have been used during clinical investigations, such as therapy. To circumvent this obstacle, recently the lytic strain 73-T
direct injection of live virus to patients through various routes of was genetically modified so that it is lytic but not pathogenic to
administration. The development of anti-NDV antibodies with chickens (Cheng et al., 2016).
subsequent re-growth of tumours has limited the applicability of The mechanisms of NDV cancer cell selectivity are not
this approach. Viral oncolysates, preparations containing plasma completely understood. Multiple mechanisms contribute to the
membrane fractions from NDV-infected cancer cells, were tested cancer cell selectivity of NDV.
as anti-cancer vaccines. Oncolysate-based vaccines are injected
under or into the skin. A new approach has also been used, 1 NDV binds to sialic acid receptors on host cells, which are
which involves the use of intact cancer cells infected with NDV overexpressed on the surface of the cancer cells. This most
as whole-cell vaccines. The tumour cells used in the vaccine are likely promotes preferential association of NDV with cancer
changed in laboratory so that they cannot multiply in the patients. cells than with normal cells.
Whole-cell vaccines stimulate the immune system better than 2 The replication of NDV requires protease cleavage of viral
oncolysates. They are given only by injection under the skin. F protein for production of infectious virus. Desirable pro-
NDV as an oncolytic virus has several advantages over other teases for activation of NDV F are overexpressed in cancer
oncolytic viruses such as poxvirus, HSV-1, adenovirus, mea- cells than in normal cells.
sles virus and reovirus. NDV is an avian virus, which avoids 3 During the process of malignization, cancer cells accumulate
the problem of pre-existing immunity in humans. NDV is many genetic changes that includes ability to produce and to
safe and highly tolerated in humans. Administration of high respond to IFN by apoptotic pathway. These abnormalities
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doses (3.3 × 10 infectious particles by intravenous route and make cancer cells highly susceptible to NDV infection (Fiola
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4.3 × 10 infectious particles by intra-tumoural route) of viru- et al., 2006; Zamarin et al., 2014). Apoptosis-resistant cancer
lent NDV to patients has shown mild side effects, with most cells are particularly sensitive to NDV-mediated cell death
common being mild fever (Fournier and Schirrmacher, 2013). (Puhlmann et al., 2010) because NDV can activate both
NDV triggers syncytium formation, which contributes to the extrinsic and intrinsic apoptotic pathways (Elankumaran et
efficiency of oncolysis, because it allows extra rounds of viral al., 2006).
replication without any exposure to host neutralizing antibod- 4 NDV is a highly immunostimulatory virus. It activates both
ies. The HN protein of NDV has neuraminidase activity which host innate and adaptive immune responses, which may be
has the potential to remove sialic acid residues from the surface responsible for the enhanced host antitumour activities.
of tumour cells, thereby exposing them to host immune cells. The immunostimulatory activity of NDV is thought to
NDV enters cells by binding to sialic acid residues, which are be mediated through the induction of type I IFN and
present on most human cancer cells, making it suitable for use chemokines, up-regulation of MHC and cell adhesion
in a broad range of cancer cell types. NDV replicates in the molecules and facilitated adhesion of lymphocytes and
cytoplasm of the cell and does not integrate into host genome, APC’s through expression of viral glycoproteins on the
which could be a problem with DNA oncolytic viruses. The surface of infected cells (Haas et al., 1998; Schirrmacher et
modular nature of NDV genome allows incorporation and al., 1999; Washburn and Schirrmacher, 2002).