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SPECT/CT imaging of oncolytic adenovirus propagation in tumours in vivo using the Na/I symporter as a reporter gene

Gene Therapy volume 14, pages 1731–1738 (2007)Cite this article

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.

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References

  1. Kaplan JM . Adenovirus-based cancer gene therapy. Curr Gene Ther 2005; 5: 595–605.

    Article  CAS  PubMed  Google Scholar 

  2. Woo Y, Adusumilli PS, Fong Y . Advances in oncolytic viral therapy. Curr Opin Investig Drugs 2006; 7: 549–559.

    CAS  PubMed  Google Scholar 

  3. 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.

    Article  CAS  PubMed  Google Scholar 

  4. 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.

    CAS  PubMed  Google Scholar 

  5. 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.

    Article  CAS  PubMed  Google Scholar 

  6. 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.

    Article  CAS  PubMed  Google Scholar 

  7. 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.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. 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.

    Article  CAS  PubMed  Google Scholar 

  9. 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.

    CAS  PubMed  Google Scholar 

  10. 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.

    Article  CAS  PubMed  Google Scholar 

  11. 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.

    Article  PubMed  Google Scholar 

  12. 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.

    Article  CAS  PubMed  Google Scholar 

  13. 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.

    Article  CAS  PubMed  Google Scholar 

  14. 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.

    Article  CAS  PubMed  Google Scholar 

  15. Chung JK . Sodium iodide symporter: its role in nuclear medicine. J Nucl Med 2002; 43: 1188–1200.

    CAS  PubMed  Google Scholar 

  16. Robbins RJ, Schlumberger MJ . The evolving role of (131)I for the treatment of differentiated thyroid carcinoma. J Nucl Med 2005; 46: 28S–37S.

    CAS  PubMed  Google Scholar 

  17. 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.

    Article  CAS  PubMed  Google Scholar 

  18. Dadachova E, Carrasco N . The Na/I symporter (NIS): imaging and therapeutic applications. Semin Nucl Med 2004; 34: 23–31.

    Article  PubMed  Google Scholar 

  19. Briat A, Vassaux G . Preclinical applications of imaging for cancer gene therapy. Expert Rev Mol Med 2006; 8: 1–19.

    Article  PubMed  Google Scholar 

  20. Vassaux G, Groot-Wassink T . In vivo noninvasive imaging for gene therapy. J Biomed Biotechnol 2003; 2: 92–101.

    Article  Google Scholar 

  21. 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.

    Article  CAS  PubMed  Google Scholar 

  22. 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.

    Article  CAS  PubMed  Google Scholar 

  23. 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.

    Article  CAS  PubMed  Google Scholar 

  24. 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.

    Article  CAS  PubMed  Google Scholar 

  25. 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.

    Article  CAS  PubMed  Google Scholar 

  26. 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.

    Article  CAS  PubMed  Google Scholar 

  27. Shah K, Jacobs A, Breakefield XO, Weissleder R . Molecular imaging of gene therapy for cancer. Gene Therapy 2004; 11: 1175–1187.

    Article  CAS  PubMed  Google Scholar 

  28. Dohan O, Carrasco N . Advances in Na(+)/I(–) symporter (NIS) research in the thyroid and beyond. Mol Cell Endocrinol 2003; 213: 59–70.

    Article  CAS  PubMed  Google Scholar 

  29. 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.

    Article  CAS  PubMed  Google Scholar 

  30. Bett AJ, Prevec L, Graham FL . Packaging capacity and stability of human adenovirus type 5 vectors. J Virol 1993; 67: 5911–5921.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 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.

    Article  CAS  PubMed  Google Scholar 

  32. 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.

    Article  CAS  PubMed  Google Scholar 

  33. Fessler SP, Young CS . Control of adenovirus early gene expression during the late phase of infection. J Virol 1998; 72: 4049–4056.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 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.

    Article  CAS  PubMed  Google Scholar 

  35. Riesco-Eizaguirre G, Santisteban P . A perspective view of sodium iodide symporter research and its clinical implications. Eur J Endocrinol 2006; 155: 495–512.

    Article  CAS  PubMed  Google Scholar 

  36. 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.

    Article  CAS  PubMed  Google Scholar 

  37. 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.

    Article  CAS  PubMed  Google Scholar 

  38. 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.

    Article  CAS  PubMed  Google Scholar 

  39. Homicsko K, Lukashev A, Iggo RD . RAD001 (everolimus) improves the efficacy of replicating adenoviruses that target colon cancer. Cancer Res 2005; 65: 6882–6890.

    Article  CAS  PubMed  Google Scholar 

  40. 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.

    Article  CAS  PubMed  Google Scholar 

  41. 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.

    Article  CAS  PubMed  Google Scholar 

  42. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. 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.

    Article  CAS  PubMed  Google Scholar 

  44. 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.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  45. 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.

    Article  CAS  PubMed  Google Scholar 

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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).

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Author notes

  1. A Merron and I Peerlinck: These authors contributed equally to this work.

Authors and Affiliations

  1. Centre for Molecular Oncology, Institute of Cancer, Queen Mary's School of Medicine and Dentistry, London, UK

    A Merron, I Peerlinck, J Burnet & G Vassaux

  2. Departamento de Bioquímica, Facultad de Ciencias Biosanitaria, Universidad Francisco de Vitoria, Madrid, Spain

    P Martin-Duque

  3. Instituto de Investigaciones Biomedicas, CSIC, c/Arturo Duperier 4, Madrid, Spain

    M Quintanilla

  4. Cancer Research UK, Nuclear Medicine Group, St Bartholomew's Hospital, London, UK

    S Mather

  5. Institute of Cancer Research, Chester Beatty Laboratories, London, UK

    M Hingorani & K Harrington

  6. Bute Medical School, University of St Andrews, Scotland, UK

    R Iggo

  7. INSERM, CIC-04 Biothérapies Hépatiques, Nantes, France

    G Vassaux

  8. Universite de Nantes, Nantes Atlantique Universite, Nantes, France

    G Vassaux

  9. Institut des Maladies de l'Appareil Digestif, Nantes, France

    G Vassaux

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Correspondence to G Vassaux.

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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

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  • DOI: https://doi.org/10.1038/sj.gt.3303043

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