Assessment of the Na/I symporter as a reporter gene to visualize oncolytic adenovirus propagation in peritoneal tumours

• Published in: European journal of nuclear medicine and molecular imaging Vol. 37; no. 7; pp. 1377 - 1385
• Main Authors: Merron, Andrew, Baril, Patrick, Martin-Duque, Pilar, de la Vieja, Antonio, Tran, Lucile, Briat, Arnaud, Harrington, Kevin J., McNeish, Iain A., Vassaux, Georges
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01.07.2010; Springer Nature B.V; Springer Verlag (Germany) [1976-....]
• Subjects: Adenoviridae - genetics; Adenoviridae - physiology; Adenovirus; Animals; Cardiology; Cell Line, Tumor; Female; Gene Expression Regulation, Neoplastic; Gene therapy; Genes, Reporter - genetics; Genome, Viral - genetics; Imaging; Injections, Intraperitoneal; Life Sciences; Medicine; Medicine & Public Health; Mice; Molecular Imaging - methods; Nuclear Medicine; Oncology; Oncolytic Viruses - genetics; Oncolytic Viruses - physiology; Original Article; Orthopedics; Ovarian cancer; Ovarian Neoplasms - genetics; Ovarian Neoplasms - therapy; Ovarian Neoplasms - virology; Peritoneal Neoplasms - genetics; Peritoneal Neoplasms - therapy; Peritoneal Neoplasms - virology; Radiology; Rodents; Symporters - genetics; Tomography; Virus Replication; Viruses; Molecular imaging; Gene therapy; Na/I symporter; SPECT/CT; Oncolytic adenovirus
• ISSN: 1619-7070; 1619-7089; 1619-7089
• DOI: 10.1007/s00259-009-1379-3

Purpose 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. Conclusion 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.