Assessment of the Na/I symporter as a reporter gene to visualize oncolytic adenovirus propagation in peritoneal tumours.
OBJECTIVE
In vivo imaging of the spread of oncolytic viruses using the Na/I symporter (NIS) has been proposed. Here, we assessed whether the presence of NIS in the viral genome affects the therapeutic efficacy of the oncolytic adenovirus dl922-947 following intraperitoneal administration, in a mouse model of peritoneal ovarian carcinoma.


METHODS
We generated AdAM7, a dl922-947 oncolytic adenovirus encoding the NIS coding sequence. Iodide uptake, NIS expression, infectivity and cell-killing activity of AdAM7, as well as that of relevant controls, were determined in vitro. In vivo, the propagation of this virus in the peritoneal cavity of tumour-bearing mice was determined using SPECT/CT imaging and its therapeutic efficacy was evaluated.


RESULTS
In vitro infection of ovarian carcinoma IGROV-1 cells with ADAM7 led to functional expression of NIS. However, the insertion of NIS into the viral genome resulted in a loss of efficacy of the virus in terms of replication and cytotoxicity. In vivo, on SPECT/CT imaging AdAM7 was only detectable in the peritoneal cavity of animals bearing peritoneal ovarian tumours for up to 5 days after intraperitoneal administration. Therapeutic experiments in vivo demonstrated that AdAM7 is as potent as its NIS-negative counterpart.


CONCLUSIONS
This study demonstrated that despite the detrimental effect observed in vitro, insertion of the reporter gene NIS in an oncolytic adenovirus did not affect its therapeutic efficacy in vivo. We conclude that NIS is a highly relevant reporter gene to monitor the fate of oncolytic adenovectors in live subjects.
Merron
Andrew
A
Centre for Molecular Oncology, Institute of Cancer, Queen Mary's School of Medicine and Dentistry, London, UK.
Baril
Patrick
P
Martin-Duque
Pilar
P
de la Vieja
Antonio
A
Tran
Lucile
L
Briat
Arnaud
A
Harrington
Kevin J
KJ
McNeish
Iain A
IA
Vassaux
Georges
G
D000256:Adenoviridae / Q000235:genetics / Q000502:physiology*; D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter / Q000235:genetics*; D016679:Genome, Viral / Q000235:genetics; D007274:Injections, Intraperitoneal; D051379:Mice; D057054:Molecular Imaging / Q000379:methods*; D050504:Oncolytic Viruses / Q000235:genetics / Q000502:physiology*; D010051:Ovarian Neoplasms / Q000235:genetics / Q000628:therapy / Q000821:virology; D010534:Peritoneal Neoplasms / Q000235:genetics / Q000628:therapy / Q000821:virology*; D027981:Symporters / Q000235:genetics*; D014779:Virus Replication; D000099209:Sodium-Iodide Symporters
D027981:Symporters; D000099209:Sodium-Iodide Symporters