Abstract
Oncolytic adenoviruses have shown some promise in cancer gene therapy. However, their efficacy in clinical trials is often limited, and additional therapeutic interventions have been proposed to increase their efficacies. In this context, molecular imaging of viral spread in tumours could provide unique information to rationalize the timing of these combinations. Here, we use the human sodium iodide symporter (hNIS) as a reporter gene in wild-type and replication-selective adenoviruses. By design, hNIS cDNA is positioned in the E3 region in a wild-type adenovirus type 5 (AdIP1) and in an adenovirus in which a promoter from the human telomerase gene (RNA component) drives E1 expression (AdAM6). Viruses show functional hNIS expression and replication in vitro and kinetics of spread of the different viruses in tumour xenografts are visualized in vivo using a small animal nano-SPECT/CT camera. The time required to reach maximal spread is 48 h for AdIP1 and 72 h for AdAM6 suggesting that genetic engineering of adenoviruses can affect their kinetics of spread in tumours. Considering that this methodology is potentially clinically applicable, we conclude that hNIS-mediated imaging of viral spread in tumours may be an important tool for combined anticancer therapies involving replicating adenoviruses.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Kaplan JM . Adenovirus-based cancer gene therapy. Curr Gene Ther 2005; 5: 595–605.
Woo Y, Adusumilli PS, Fong Y . Advances in oncolytic viral therapy. Curr Opin Investig Drugs 2006; 7: 549–559.
Komarova S, Kawakami Y, Stoff-Khalili MA, Curiel DT, Pereboeva L . Mesenchymal progenitor cells as cellular vehicles for delivery of oncolytic adenoviruses. Mol Cancer Ther 2006; 5: 755–766.
Wein LM, Wu JT, Kirn DH . Validation and analysis of a mathematical model of a replication-competent oncolytic virus for cancer treatment: implications for virus design and delivery. Cancer Res 2003; 63: 1317–1324.
Vassaux G, Martin-Duque P . Use of suicide genes for cancer gene therapy: study of the different approaches. Expert Opin Biol Ther 2004; 4: 519–530.
Dilley J, Reddy S, Ko D, Nguyen N, Rojas G, Working P et al. Oncolytic adenovirus CG7870 in combination with radiation demonstrates synergistic enhancements of antitumor efficacy without loss of specificity. Cancer Gene Ther 2005; 12: 715–722.
Geoerger B, Grill J, Opolon P, Morizet J, Aubert G, Lecluse Y et al. Potentiation of radiation therapy by the oncolytic adenovirus dl1520 (ONYX-015) in human malignant glioma xenografts. Br J Cancer 2003; 89: 577–584.
Schepelmann S, Ogilvie LM, Hedley D, Friedlos F, Martin J, Scanlon I et al. Suicide gene therapy of human colon carcinoma xenografts using an armed oncolytic adenovirus expressing carboxypeptidase G2. Cancer Res 2007; 67: 4949–4955.
Wildner O, Morris JC . The role of the E1B 55 kDa gene product in oncolytic adenoviral vectors expressing herpes simplex virus-tk: assessment of antitumor efficacy and toxicity. Cancer Res 2000; 60: 4167–4174.
Lamfers ML, Fulci G, Gianni D, Tang Y, Kurozumi K, Kaur B et al. Cyclophosphamide increases transgene expression mediated by an oncolytic adenovirus in glioma-bearing mice monitored by bioluminescence imaging. Mol Ther 2006; 14: 779–788.
Sarkioja M, Kanerva A, Salo J, Kangasniemi L, Eriksson M, Raki M et al. Noninvasive imaging for evaluation of the systemic delivery of capsid-modified adenoviruses in an orthotopic model of advanced lung cancer. Cancer 2006; 107: 1578–1588.
Le LP, Le HN, Dmitriev IP, Davydova JG, Gavrikova T, Yamamoto S et al. Dynamic monitoring of oncolytic adenovirus in vivo by genetic capsid labeling. J Natl Cancer Inst 2006; 98: 203–214.
Ono HA, Le LP, Davydova JG, Gavrikova T, Yamamoto M . Noninvasive visualization of adenovirus replication with a fluorescent reporter in the E3 region. Cancer Res 2005; 65: 10154–10158.
Kanerva A, Zinn KR, Peng KW, Ranki T, Kangasniemi L, Chaudhuri TR et al. Noninvasive dual modality in vivo monitoring of the persistence and potency of a tumor targeted conditionally replicating adenovirus. Gene Therapy 2005; 12: 87–94.
Chung JK . Sodium iodide symporter: its role in nuclear medicine. J Nucl Med 2002; 43: 1188–1200.
Robbins RJ, Schlumberger MJ . The evolving role of (131)I for the treatment of differentiated thyroid carcinoma. J Nucl Med 2005; 46: 28S–37S.
Spitzweg C, Harrington KJ, Pinke LA, Vile RG, Morris JC . Clinical review 132: The sodium iodide symporter and its potential role in cancer therapy. J Clin Endocrinol Metab 2001; 86: 3327–3335.
Dadachova E, Carrasco N . The Na/I symporter (NIS): imaging and therapeutic applications. Semin Nucl Med 2004; 34: 23–31.
Briat A, Vassaux G . Preclinical applications of imaging for cancer gene therapy. Expert Rev Mol Med 2006; 8: 1–19.
Vassaux G, Groot-Wassink T . In vivo noninvasive imaging for gene therapy. J Biomed Biotechnol 2003; 2: 92–101.
Haberkorn U, Altmann A, Eisenhut M . Functional genomics and proteomics—the role of nuclear medicine. Eur J Nucl Med Mol Imaging 2002; 29: 115–132.
Groot-Wassink T, Aboagye EO, Glaser M, Lemoine NR, Vassaux G . Adenovirus biodistribution and noninvasive imaging of gene expression in vivo by positron emission tomography using human sodium/iodide symporter as reporter gene. Hum Gene Ther 2002; 13: 1723–1735.
Groot-Wassink T, Aboagye EO, Wang Y, Lemoine NR, Keith WN, Vassaux G . Noninvasive imaging of the transcriptional activities of human telomerase promoter fragments in mice. Cancer Res 2004; 64: 4906–4911.
Groot-Wassink T, Aboagye EO, Wang Y, Lemoine NR, Reader AJ, Vassaux G . Quantitative imaging of Na/I symporter transgene expression using positron emission tomography in the living animal. Mol Ther 2004; 9: 436–442.
Faivre J, Clerc J, Gerolami R, Herve J, Longuet M, Liu B et al. Long-term radioiodine retention and regression of liver cancer after sodium iodide symporter gene transfer in wistar rats. Cancer Res 2004; 64: 8045–8051.
Marsee DK, Shen DH, MacDonald LR, Vadysirisack DD, Lin X, Hinkle G et al. Imaging of metastatic pulmonary tumors following NIS gene transfer using single photon emission computed tomography. Cancer Gene Ther 2004; 11: 121–127.
Shah K, Jacobs A, Breakefield XO, Weissleder R . Molecular imaging of gene therapy for cancer. Gene Therapy 2004; 11: 1175–1187.
Dohan O, Carrasco N . Advances in Na(+)/I(–) symporter (NIS) research in the thyroid and beyond. Mol Cell Endocrinol 2003; 213: 59–70.
Bilsland AE, Merron A, Vassaux G, Keith WN . Modulation of telomerase promoter tumor selectivity in the context of oncolytic adenoviruses. Cancer Res 2007; 67: 1299–1307.
Bett AJ, Prevec L, Graham FL . Packaging capacity and stability of human adenovirus type 5 vectors. J Virol 1993; 67: 5911–5921.
Hawkins LK, Johnson L, Bauzon M, Nye JA, Castro D, Kitzes GA et al. Gene delivery from the E3 region of replicating human adenovirus: evaluation of the 6.7 K/gp19 K region. Gene Therapy 2001; 8: 1123–1131.
Wang Y, Hallden G, Hill R, Anand A, Liu TC, Francis J et al. E3 gene manipulations affect oncolytic adenovirus activity in immunocompetent tumor models. Nat Biotechnol 2003; 21: 1328–1335.
Fessler SP, Young CS . Control of adenovirus early gene expression during the late phase of infection. J Virol 1998; 72: 4049–4056.
Majem M, Cascallo M, Bayo-Puxan N, Mesia R, Germa JR, Alemany R . Control of E1A under an E2F-1 promoter insulated with the myotonic dystrophy locus insulator reduces the toxicity of oncolytic adenovirus Ad-Delta24RGD. Cancer Gene Ther 2006; 13: 696–705.
Riesco-Eizaguirre G, Santisteban P . A perspective view of sodium iodide symporter research and its clinical implications. Eur J Endocrinol 2006; 155: 495–512.
Dingli D, Peng KW, Harvey ME, Greipp PR, O'Connor MK, Cattaneo R et al. Image-guided radiovirotherapy for multiple myeloma using a recombinant measles virus expressing the thyroidal sodium iodide symporter. Blood 2004; 103: 1641–1646.
Blechacz B, Splinter PL, Greiner S, Myers R, Peng KW, Federspiel MJ et al. Engineered measles virus as a novel oncolytic viral therapy system for hepatocellular carcinoma. Hepatology 2006; 44: 1465–1477.
Gagnebin J, Brunori M, Otter M, Juillerat-Jeanneret L, Monnier P, Iggo R . A photosensitising adenovirus for photodynamic therapy. Gene Therapy 1999; 6: 1742–1750.
Homicsko K, Lukashev A, Iggo RD . RAD001 (everolimus) improves the efficacy of replicating adenoviruses that target colon cancer. Cancer Res 2005; 65: 6882–6890.
Rowntree RK, Vassaux G, McDowell TL, Howe S, McGuigan A, Phylactides M et al. An element in intron 1 of the CFTR gene augments intestinal expression in vivo. Hum Mol Genet 2001; 10: 1455–1464.
Vassaux G, Manson AL, Huxley C . Copy number-dependent expression of a YAC-cloned human CFTR gene in a human epithelial cell line. Gene Therapy 1997; 4: 618–623.
He TC, Zhou S, da Costa LT, Yu J, Kinzler KW, Vogelstein B . A simplified system for generating recombinant adenoviruses. Proc Natl Acad Sci USA 1998; 95: 2509–2514.
Martinico SC, Jezzard S, Sturt NJ, Michils G, Tejpar S, Phillips RK et al. Assessment of endostatin gene therapy for familial adenomatous polyposis-related desmoid tumors. Cancer Res 2006; 66: 8233–8240.
Stoll V, Calleja V, Vassaux G, Downward J, Lemoine NR . Dominant negative inhibitors of signalling through the phosphoinositol 3-kinase pathway for gene therapy of pancreatic cancer. Gut 2005; 54: 109–116.
Wang Y, Groot-Wassink T, Lemoine NR, Vassaux G . Cellular characterization of the tropism of recombinant adenovirus for the adrenal glands. Eur J Clin Invest 2003; 33: 794–798.
Acknowledgements
We thank Dr Jhiang for providing the hNIS cDNA. This work is supported by grants from Cancer Research UK, the Medical Research Council, INSERM and by Grant 0607-3D1615-66/AO INSERM from the French National Cancer Institute (INCa).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Merron, A., Peerlinck, I., Martin-Duque, P. et al. SPECT/CT imaging of oncolytic adenovirus propagation in tumours in vivo using the Na/I symporter as a reporter gene. Gene Ther 14, 1731–1738 (2007). https://doi.org/10.1038/sj.gt.3303043
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.gt.3303043
Keywords
This article is cited by
-
[18F]tetrafluoroborate-PET/CT enables sensitive tumor and metastasis in vivo imaging in a sodium iodide symporter-expressing tumor model
Scientific Reports (2017)
-
Perfusion Pressure Is a Critical Determinant of the Intratumoral Extravasation of Oncolytic Viruses
Molecular Therapy (2016)
-
Sequence-defined cMET/HGFR-targeted Polymers as Gene Delivery Vehicles for the Theranostic Sodium Iodide Symporter (NIS) Gene
Molecular Therapy (2016)
-
Molecular imaging of oncolytic viral therapy
Molecular Therapy - Oncolytics (2014)
-
Sodium iodide symporter (NIS)-mediated radiovirotherapy of hepatocellular cancer using a conditionally replicating adenovirus
Gene Therapy (2013)