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:

Evaluation of apoptogenic adenovirus type 5 oncolytic vectors in a Syrian hamster head and neck cancer model

Cancer Gene Therapy volume 21, pages 228–237 (2014)Cite this article

Subjects

Abstract

Human adenovirus (HAdV) vectors are intensely investigated for virotherapy of a wide variety of human cancers. Here, we have evaluated the effect of two apoptogenic HAdV5 vectors in an immunocompetent Syrian hamster animal model of head and neck cancer. We established two cell lines of hamster cheek pouch squamous cell carcinomas, induced by treatment with 9,10-dimethyl-1,2-benzanthracene. These cell lines, when infected with HAdV5 mutants lp11w and lp11w/Δ55 K (which are defective in the expression of either E1B-19 K alone or both E1B-19 K and E1B-55 K proteins) exhibited enhanced apoptotic and cytotoxic responses. The cheek pouch tumor cells transplanted either subcutaneously at the flanks or in the cheek pouches of hamsters readily formed tumors. Intratumoral administration of HAdV5-E1B mutants efficiently suppressed the growth of tumors at both sites. Histological examination of orthotopic tumors revealed reduced vascularity and the expression of the viral fiber antigen in virus-administered cheek pouch tumors. These tumors also exhibited increased caspase-3 levels, suggesting that virus-induced apoptosis may contribute to tumor growth suppression. Our results suggest that the apoptogenic HAdV5 vectors may have utility for the treatment of human head and neck cancers.

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
Figure 7

Similar content being viewed by others

References

  1. Ries L, Young J, Keel G, Eisner M, Lin Y, Horner M SEER Survival Monograph: Cancer Survival Among Adults: US SEER Program 1998-2001, Patient and Tumor Characteristics. National Cancer Institute, SEER Program; NIH Pub. No. 07-6215: Bethesda, MD, 2007.

  2. Huang SM, Bock JM, Harari PM . Epidermal growth factor receptor blockade with C225 modulates proliferation, apoptosis, and radiosensitivity in squamous cell carcinomas of the head and neck. Cancer Res 1999; 59: 1935–1940.

    CAS  PubMed  Google Scholar 

  3. Bonner JA, Harari PM, Giralt J, Azarnia N, Shin DM, Cohen RB et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 2006; 354: 567–578.

    Article  CAS  Google Scholar 

  4. Baselga J, Schoffski P, Rojo F, Dumez H, Ramos FJ, Macarulla T et al. A phase I pharmacokinetic (PK) and molecular pharmacodynamic (PD) study of the combination of two anti-EGFR therapies, the monoclonal antibody (MAb) cetuximab (C) and the tyrosine kinase inhibitor (TKI) gefitinib (G), in patients (pts) with advanced colorectal (CRC), head and neck (HNC) and non-small cell lung cancer (NSCLC). J Clin Oncol 2006; 24: 122s–122s.

    Article  Google Scholar 

  5. Kalyankrishna S, Grandis JR . Epidermal growth factor receptor biology in head and neck cancer. J Clin Oncol 2006; 24: 2666–2672.

    Article  CAS  Google Scholar 

  6. Reuter CW, Morgan MA, Eckardt A . Targeting EGF-receptor-signalling in squamous cell carcinomas of the head and neck. Br J Cancer 2007; 96: 408–416.

    Article  CAS  Google Scholar 

  7. Sharma H, Sen S, Lo Muzio L, Mariggio A, Singh N . Antisense-mediated downregulation of anti-apoptotic proteins induces apoptosis and sensitizes head and neck squamous cell carcinoma cells to chemotherapy. Cancer Biol Ther 2005; 4: 720–727.

    Article  CAS  Google Scholar 

  8. Bauer JA, Trask DK, Kumar B, Los G, Castro J, Lee JS et al. Reversal of cisplatin resistance with a BH3 mimetic, (-)-gossypol, in head and neck cancer cells: role of wild-type p53 and Bcl-xL. Mol Cancer Ther 2005; 4: 1096–1104.

    Article  CAS  Google Scholar 

  9. Vijayalingam S, Subramanian T, Ryerse J, Varvares M, Chinnadurai G . Down-regulation of multiple cell survival proteins in head and neck cancer cells by an apoptogenic mutant of adenovirus type 5. Virology 2009; 392: 62–72.

    Article  CAS  Google Scholar 

  10. Blackford AN, Grand RJ . Adenovirus E1B 55-kilodalton protein: multiple roles in viral infection and cell transformation. J Virol 2009; 83: 4000–4012.

    Article  CAS  Google Scholar 

  11. O’Shea CC, Johnson L, Bagus B, Choi S, Nicholas C, Shen A et al. Late viral RNA export, rather than p53 inactivation, determines ONYX-015 tumor selectivity. Cancer Cell 2004; 6: 611–623.

    Article  Google Scholar 

  12. Khuri FR, Nemunaitis J, Ganly I, Arseneau J, Tannock IF, Romel L et al. a controlled trial of intratumoral ONYX-015, a selectively-replicating adenovirus, in combination with cisplatin and 5-fluorouracil in patients with recurrent head and neck cancer. Nat Med 2000; 6: 879–885.

    Article  CAS  Google Scholar 

  13. Chia MC, Shi W, Li JH, Sanchez O, Strathdee CA, Huang D et al. A conditionally replicating adenovirus for nasopharyngeal carcinoma gene therapy. Mol Ther 2004; 9: 804–817.

    Article  CAS  Google Scholar 

  14. Toivonen R, Suominen E, Grenman R, Savontaus M . Retargeting improves the efficacy of a telomerase-dependent oncolytic adenovirus for head and neck cancer. Oncol Rep 2009; 21: 165–171.

    PubMed  Google Scholar 

  15. Blackwell JL, Miller CR, Douglas JT, Li H, Reynolds PN, Carroll WR et al. Retargeting to EGFR enhances adenovirus infection efficiency of squamous cell carcinoma. Arch Otolaryngol Head Neck Surg 1999; 125: 856–863.

    Article  CAS  Google Scholar 

  16. Boyle JO, Hakim J, Koch W, van der Riet P, Hruban RH, Roa RA et al. The incidence of p53 mutations increases with progression of head and neck cancer. Cancer Res 1993; 53: 4477–4480.

    CAS  Google Scholar 

  17. Pan JJ, Zhang SW, Chen CB, Xiao SW, Sun Y, Liu CQ et al. Effect of recombinant adenovirus-p53 combined with radiotherapy on long-term prognosis of advanced nasopharyngeal carcinoma. J Clin Oncol 2009; 27: 799–804.

    Article  Google Scholar 

  18. Nemunaitis J . Head and neck cancer: response to p53-based therapeutics. Head Neck 2011; 33: 131–134.

    Article  Google Scholar 

  19. Peng Z . Current status of gendicine in China: recombinant human Ad-p53 agent for treatment of cancers. Hum Gene Ther 2005; 16: 1016–1027.

    Article  CAS  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  Google Scholar 

  21. Bortolanza S, Alzuguren P, Bunuales M, Qian C, Prieto J, Hernandez-Alcoceba R . Human adenovirus replicates in immunocompetent models of pancreatic cancer in Syrian hamsters. Hum Gene Ther 2007; 18: 681–690.

    Article  CAS  Google Scholar 

  22. Hasegawa N, Abei M, Yokoyama KK, Fukuda K, Seo E, Kawashima R et al. Cyclophosphamide enhances antitumor efficacy of oncolytic adenovirus expressing uracil phosphoribosyltransferase (UPRT) in immunocompetent Syrian hamsters. Int J Cancer 2013; 133: 1479–1488.

    Article  CAS  Google Scholar 

  23. Spencer JF, Sagartz JE, Wold WS, Toth K . New pancreatic carcinoma model for studying oncolytic adenoviruses in the permissive Syrian hamster. Cancer Gene Ther 2009; 16: 912–922.

    Article  CAS  Google Scholar 

  24. Adams J, Heintz P, Gross N, Andersen P, Everts E, Wax M et al. Acid/pepsin promotion of carcinogenesis in the hamster cheek pouch. Arch Otolaryngol Head Neck Surg 2000; 126: 405–409.

    Article  CAS  Google Scholar 

  25. Manoharan S, Balakrishnan S, Menon VP, Alias LM, Reena AR . Chemopreventive efficacy of curcumin and piperine during 7,12-dimethylbenz[a]anthracene-induced hamster buccal pouch carcinogenesis. Singapore Med J 2009; 50: 139–146.

    CAS  PubMed  Google Scholar 

  26. Min BM, Kim K, Cherrick HM, Park NH . Three cell lines from hamster buccal pouch tumors induced by topical 7,12-dimethylbenz(a)anthracene, alone or in conjunction with herpes simplex virus inoculation. In Vitro Cell Dev Biol 1991; 27A: 128–136.

    Article  CAS  Google Scholar 

  27. Subramanian T, Vijayalingam S, Chinnadurai G . Genetic identification of adenovirus type 5 genes that influence viral spread. J Virol 2006; 80: 2000–2012.

    Article  CAS  Google Scholar 

  28. Gonzalez R, Huang W, Finnen R, Bragg C, Flint SJ . Adenovirus E1B 55-kilodalton protein is required for both regulation of mRNA export and efficient entry into the late phase of infection in normal human fibroblasts. J Virol 2006; 80: 964–974.

    Article  CAS  Google Scholar 

  29. Slaga TJ, Gimenez-Conti IB . An animal model for oral cancer. J Natl Cancer Inst Monogr 1992; 13: 55–60.

    Google Scholar 

  30. Wold WS, Toth K . Chapter three—Syrian hamster as an animal model to study oncolytic adenoviruses and to evaluate the efficacy of antiviral compounds. Adv Cancer Res 2012; 115: 69–92.

    Article  CAS  Google Scholar 

  31. Bongers V, Braakhuis BJ, Snow GB . Circulating fragments of cytokeratin 19 in patients with head and neck squamous cell carcinoma. Clin Otolaryngol Allied Sci 1995; 20: 479–482.

    Article  CAS  Google Scholar 

  32. Xu XC, Lee JS, Lippman SM, Ro JY, Hong WK, Lotan R . Increased expression of cytokeratins CK8 and CK19 is associated with head and neck carcinogenesis. Cancer Epidemiol Biomarkers Prev 1995; 4: 871–876.

    CAS  PubMed  Google Scholar 

  33. Becker MT, Shores CG, Yu KK, Yarbrough WG . Molecular assay to detect metastatic head and neck squamous cell carcinoma. Arch Otolaryngol Head Neck Surg 2004; 130: 21–27.

    Article  Google Scholar 

  34. Chinnadurai G . Control of apoptosis by human adenovirus genes. Semin Virol 1998; 8: 399–408.

    Article  CAS  Google Scholar 

  35. Cuconati A, White E . Viral homologs of BCL-2: role of apoptosis in the regulation of virus infection. Genes Dev 2002; 16: 2465–2478.

    Article  CAS  Google Scholar 

  36. Thomas MA, Spencer JF, Toth K, Sagartz JE, Phillips NJ, Wold WS . Immunosuppression enhances oncolytic adenovirus replication and antitumor efficacy in the Syrian hamster model. Mol Ther 2008; 16: 1665–1673.

    Article  CAS  Google Scholar 

  37. Young BA, Spencer JF, Ying B, Tollefson AE, Toth K, Wold WS . The role of cyclophosphamide in enhancing antitumor efficacy of an adenovirus oncolytic vector in subcutaneous Syrian hamster tumors. Cancer Gene Ther 2013; 20: 521–530.

    Article  CAS  Google Scholar 

  38. Rowinsky EK . The erbB family: targets for therapeutic development against cancer and therapeutic strategies using monoclonal antibodies and tyrosine kinase inhibitors. Annu Rev Med 2004; 55: 433–457.

    Article  CAS  Google Scholar 

  39. Herbst RS, Fukuoka M, Baselga J . Gefitinib—a novel targeted approach to treating cancer. Nat Rev Cancer 2004; 4: 956–965.

    Article  CAS  Google Scholar 

  40. Carlin CR, Tollefson AE, Brady HA, Hoffman BL, Wold WS . Epidermal growth factor receptor is down-regulated by a 10,400 MW protein encoded by the E3 region of adenovirus. Cell 1989; 57: 135–144.

    Article  CAS  Google Scholar 

  41. Tollefson AE, Stewart AR, Yei SP, Saha SK, Wold WS . The 10,400- and 14,500-dalton proteins encoded by region E3 of adenovirus form a complex and function together to down-regulate the epidermal growth factor receptor. J Virol 1991; 65: 3095–3105.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Flinterman MB, Mymryk JS, Klanrit P, Yousef AF, Lowe SW, Caldas C et al. p400 function is required for the adenovirus E1A-mediated suppression of EGFR and tumour cell killing. Oncogene 2007; 26: 6863–6874.

    Article  CAS  Google Scholar 

  43. Flinterman M, Gaken J, Farzaneh F, Tavassoli M . E1A-mediated suppression of EGFR expression and induction of apoptosis in head and neck squamous carcinoma cell lines. Oncogene 2003; 22: 1965–1977.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by research grants CA-33616 and CA-84941 from the National Cancer Institute and by a grant from the Lottie Caroline Hardy Charitable Trust. We thank WSM Wold and Karoly Toth for their comments on the manuscript. We thank Jenni Franey and Anna Cline for their help with animal work.

Author information

Author notes

  1. S Vijayalingam and M Kuppuswamy: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute for Molecular Virology, Saint Louis University School of Medicine, St Louis, MO, USA

    S Vijayalingam, M Kuppuswamy, T Subramanian & G Chinnadurai

  2. Department of Comparative Medicine, Saint Louis University School of Medicine, St Louis, MO, USA

    F F Strebeck & C L West

  3. Department of Otolaryngology, Head and Neck Surgery, Saint Louis University Cancer Center, St Louis, MO, USA

    M Varvares

Authors
  1. S Vijayalingam
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M Kuppuswamy
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. T Subramanian
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. F F Strebeck
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. C L West
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. M Varvares
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. G Chinnadurai
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to M Varvares or G Chinnadurai.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Vijayalingam, S., Kuppuswamy, M., Subramanian, T. et al. Evaluation of apoptogenic adenovirus type 5 oncolytic vectors in a Syrian hamster head and neck cancer model. Cancer Gene Ther 21, 228–237 (2014). https://doi.org/10.1038/cgt.2014.22

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/cgt.2014.22

This article is cited by

Search

Advanced search

Quick links