Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Biodistribution of an oncolytic adenovirus after intracranial injection in permissive animals: a comparative study of Syrian hamsters and cotton rats

Cancer Gene Therapy volume 16, pages 362–372 (2009)Cite this article

Abstract

Conditionally replicative adenoviruses (CRAds) are often evaluated in mice; however, normal and cancerous mouse tissues are poorly permissive for human CRAds. As the cotton rat (CR) is a semipermissive animal and the Syrian hamster (SH) is a fully permissive model for adenoviral replication, we compared them in a single study following intracranial (i.c.) injection of a novel glioma-targeting CRAd. Viral genomic copies were quantified by real-time PCR in brain, blood, liver and lung. The studies were corroborated by immunohistochemical, serological and immunological assays. CR had a multiple log higher susceptibility for adenoviral infection than SH. A similar amount of genomic copies of CRAd-Survivin-pk7 and human adenovirus serotype 5 (AdWT) was found in the brain of CR and in all organs from SH. In blood and lung of CR, AdWT had more genomic copies than CRAd-Survivin-pk7 in some of the time points studied. Viral antigens were confirmed in brain slices, an elevation of serum transaminases was observed in both models, and an increase in anti-adenoviral antibodies was detected in SH sera. In conclusion, CR represents a sensitive model for studying biodistribution of CRAds after i.c. delivery, allowing for the detection of differences in the replication of CRAd-Survivin-pk7 and AdWT that were not evident in SH.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  1. Jiang H, McCormick F, Lang FF, Gomez-Manzano C, Fueyo J . Oncolytic adenoviruses as antiglioma agents. Expert Rev Anticancer Ther 2006; 6: 697–708.

    Article  CAS  PubMed  Google Scholar 

  2. Sonabend AM, Ulasov IV, Han Y, Lesniak MS . Oncolytic adenoviral therapy for glioblastoma multiforme. Neurosurg Focus 2006; 20: E19.

    Article  PubMed  Google Scholar 

  3. Ulasov IV, Tyler MA, Han Y, Glasgow JN, Lesniak MS . Novel recombinant adenoviral vector that targets the interleukin-13 receptor alpha2 chain permits effective gene transfer to malignant glioma. Hum Gene Ther 2007; 18: 118–129.

    Article  CAS  PubMed  Google Scholar 

  4. Tyler MA, Ulasov IV, Borovjagin A, Sonabend AM, Khramtsov A, Han Y et al. Enhanced transduction of malignant glioma with a double targeted Ad5/3-RGD fiber-modified adenovirus. Mol Cancer Ther 2006; 5: 2408–2416.

    Article  CAS  PubMed  Google Scholar 

  5. Sebestyen Z, de Vrij J, Magnusson M, Debets R, Willemsen R . An oncolytic adenovirus redirected with a tumor-specific T-cell receptor. Cancer Res 2007; 67: 11309–11316.

    Article  CAS  PubMed  Google Scholar 

  6. Wohlfahrt ME, Beard BC, Lieber A, Kiem HP . A capsid-modified, conditionally replicating oncolytic adenovirus vector expressing TRAIL Leads to enhanced cancer cell killing in human glioblastoma models. Cancer Res 2007; 67: 8783–8790.

    Article  CAS  PubMed  Google Scholar 

  7. Ulasov IV, Rivera AA, Nettelbeck DM, Rivera LB, Mathis JM, Sonabend AM et al. An oncolytic adenoviral vector carrying the tyrosinase promoter for glioma gene therapy. Int J Oncol 2007; 31: 1177–1185.

    CAS  PubMed  Google Scholar 

  8. Van Houdt WJ, Haviv YS, Lu B, Wang M, Rivera AA, Ulasov IV et al. The human survivin promoter: a novel transcriptional targeting strategy for treatment of glioma. J Neurosurg 2006; 104: 583–592.

    Article  CAS  PubMed  Google Scholar 

  9. Ulasov IV, Rivera AA, Sonabend AM, Rivera LB, Wang M, Zhu ZB et al. Comparative evaluation of survivin, midkine and CXCR4 promoters for transcriptional targeting of glioma gene therapy. Cancer Biol Ther 2007; 6: 679–685.

    Article  CAS  PubMed  Google Scholar 

  10. Fueyo J, Gomez-Manzano C, Alemany R, Lee PS, McDonnell TJ, Mitlianga P et al. A mutant oncolytic adenovirus targeting the Rb pathway produces anti-glioma effect in vivo. Oncogene 2000; 19: 2–12.

    Article  CAS  PubMed  Google Scholar 

  11. Xia ZJ, Chang JH, Zhang L, Jiang WQ, Guan ZZ, Liu JW et al. [Phase III randomized clinical trial of intratumoral injection of E1B gene-deleted adenovirus (H101) combined with cisplatin-based chemotherapy in treating squamous cell cancer of head and neck or esophagus.]. Ai Zheng 2004; 23: 1666–1670.

    PubMed  Google Scholar 

  12. Garber K . China approves world's first oncolytic virus therapy for cancer treatment. J Natl Cancer Inst 2006; 98: 298–300.

    Article  PubMed  Google Scholar 

  13. Ulasov IV, Zhu ZB, Tyler MA, Han Y, Rivera AA, Khramtsov A et al. Survivin-driven and fiber-modified oncolytic adenovirus exhibits potent antitumor activity in established intracranial glioma. Hum Gene Ther 2007; 18: 589–602.

    Article  CAS  PubMed  Google Scholar 

  14. Zheng S, Ulasov IV, Han Y, Tyler MA, Zhu ZB, Lesniak MS . Fiber-knob modifications enhance adenoviral tropism and gene transfer in malignant glioma. J Gene Med 2007; 9: 151–160.

    Article  CAS  PubMed  Google Scholar 

  15. Nandi S, Ulasov IV, Tyler M, Sugihara AQ, Molinero L, Han Y et al. Low-dose radiation enhances survivin-mediated virotherapy against malignant glioma stem cells. Cancer Res 2008; 68: 5778–5784.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Ginsberg HS, Moldawer LL, Sehgal PB, Redington M, Kilian PL, Chanock RM et al. A mouse model for investigating the molecular pathogenesis of adenovirus pneumonia. Proc Natl Acad Sci USA 1991; 88: 1651–1655.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Hjorth RN, Bonde GM, Pierzchala WA, Vernon SK, Wiener FP, Levner MH et al. A new hamster model for adenoviral vaccination. Arch Virol 1988; 100: 279–283.

    Article  CAS  PubMed  Google Scholar 

  18. Duncan SJ, Gordon FC, Gregory DW, McPhie JL, Postlethwaite R, White R et al. Infection of mouse liver by human adenovirus type 5. J Gen Virol 1978; 40: 45–61.

    Article  CAS  PubMed  Google Scholar 

  19. Toth K, Spencer JF, Tollefson AE, Kuppuswamy M, Doronin K, Lichtenstein DL et al. Cotton rat tumor model for the evaluation of oncolytic adenoviruses. Hum Gene Ther 2005; 16: 139–146.

    Article  CAS  PubMed  Google Scholar 

  20. Thomas MA, Spencer JF, La Regina MC, Dhar D, Tollefson AE, Toth K et al. Syrian hamster as a permissive immunocompetent animal model for the study of oncolytic adenovirus vectors. Cancer Res 2006; 66: 1270–1276.

    Article  CAS  PubMed  Google Scholar 

  21. Toth K, Spencer JF, Wold WS . Immunocompetent, semi-permissive cotton rat tumor model for the evaluation of oncolytic adenoviruses. Methods Mol Med 2007; 130: 157–168.

    PubMed  Google Scholar 

  22. Thomas MA, Spencer JF, Wold WS . Use of the Syrian hamster as an animal model for oncolytic adenovirus vectors. Methods Mol Med 2007; 130: 169–183.

    CAS  PubMed  Google Scholar 

  23. Hsu W, Lesniak MS, Tyler B, Brem H . Local delivery of interleukin-2 and adriamycin is synergistic in the treatment of experimental malignant glioma. J Neurooncol 2005; 74: 135–140.

    Article  CAS  PubMed  Google Scholar 

  24. Lesniak MS, Gabikian P, Tyler BM, Pardoll DM, Brem H . Dexamethasone mediated inhibition of local IL-2 immunotherapy is dose dependent in experimental brain tumors. J Neurooncol 2004; 70: 23–28.

    Article  PubMed  Google Scholar 

  25. Lesniak MS, Upadhyay U, Goodwin R, Tyler B, Brem H . Local delivery of doxorubicin for the treatment of malignant brain tumors in rats. Anticancer Res 2005; 25: 3825–3831.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Zhu ZB, Chen Y, Makhija SK, Lu B, Wang M, Rivera AA et al. Survivin promoter-based conditionally replicative adenoviruses target cholangiocarcinoma. Int J Oncol 2006; 29: 1319–1329.

    CAS  PubMed  Google Scholar 

  27. Wu H, Han T, Lam JT, Leath CA, Dmitriev I, Kashentseva E et al. Preclinical evaluation of a class of infectivity-enhanced adenoviral vectors in ovarian cancer gene therapy. Gene Ther 2004; 11: 874–878.

    Article  PubMed  Google Scholar 

  28. Graham FL, Smiley J, Russell WC, Nairn R . Characteristics of a human cell line transformed by DNA from human adenovirus type 5. J Gen Virol 1977; 36: 59–74.

    Article  CAS  PubMed  Google Scholar 

  29. Reid T, Galanis E, Abbruzzese J, Sze D, Wein LM, Andrews J et al. Hepatic arterial infusion of a replication-selective oncolytic adenovirus (dl1520): phase II viral, immunologic, and clinical endpoints. Cancer Res 2002; 62: 6070–6079.

    CAS  PubMed  Google Scholar 

  30. Reid T, Galanis E, Abbruzzese J, Sze D, Andrews J, Romel L et al. Intra-arterial administration of a replication-selective adenovirus (dl1520) in patients with colorectal carcinoma metastatic to the liver: a phase I trial. Gene Ther 2001; 8: 1618–1626.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Lin X, Huang H, Li S, Li H, Li Y, Cao Y et al. A phase I clinical trial of an adenovirus-mediated endostatin gene (E10A) in patients with solid tumors. Cancer Biol Ther 2007; 6: 648–653.

    Article  CAS  PubMed  Google Scholar 

  32. Galanis E, Okuno SH, Nascimento AG, Lewis BD, Lee RA, Oliveira AM et al. Phase I-II trial of ONYX-015 in combination with MAP chemotherapy in patients with advanced sarcomas. Gene Ther 2005; 12: 437–445.

    Article  CAS  PubMed  Google Scholar 

  33. Nemunaitis J, Senzer N, Sarmiento S, Zhang YA, Arzaga R, Sands B et al. A phase I trial of intravenous infusion of ONYX-015 and enbrel in solid tumor patients. Cancer Gene Ther 2007; 14: 885–893.

    Article  CAS  PubMed  Google Scholar 

  34. Small EJ, Carducci MA, Burke JM, Rodriguez R, Fong L, van Ummersen L et al. A phase I trial of intravenous CG7870, a replication-selective, prostate-specific antigen-targeted oncolytic adenovirus, for the treatment of hormone-refractory, metastatic prostate cancer. Mol Ther 2006; 14: 107–117.

    Article  CAS  PubMed  Google Scholar 

  35. Miller HI . Gene therapy on trial. Science 2000; 287: 591–592.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We are grateful to the animal facility at the University of Chicago for their advice and technical support. In addition, we acknowledge the support of Ms Terri Li from the immunohistochemistry facility at the University of Chicago. This work was supported by the National Cancer Institute (R01-CA122930, MSL), the National Institute of Neurological Disorders and Stroke (K08-NS046430, MSL), The Alliance for Cancer Gene Therapy Young Investigator Award (MSL) and the American Cancer Society (RSG-07-276-01-MGO, MSL).

Author information

Authors and Affiliations

  1. The Brain Tumor Center, The University of Chicago, Chicago, IL, USA

    A M Sonabend, I V Ulasov, Y Han, C E Rolle, S Nandi, M A Tyler & M S Lesniak

  2. Department of Health Studies, The University of Chicago, Chicago, IL, USA

    D Cao

Authors
  1. A M Sonabend
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. I V Ulasov
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Y Han
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. C E Rolle
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. S Nandi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. D Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. M A Tyler
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. M S Lesniak
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M S Lesniak.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sonabend, A., Ulasov, I., Han, Y. et al. Biodistribution of an oncolytic adenovirus after intracranial injection in permissive animals: a comparative study of Syrian hamsters and cotton rats. Cancer Gene Ther 16, 362–372 (2009). https://doi.org/10.1038/cgt.2008.80

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/cgt.2008.80

Keywords

This article is cited by

Search

Advanced search

Quick links