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The effect of hypoxia on the uptake, replication and lytic potential of group B adenovirus type 3 (Ad3) and type 11p (Ad11p)

Gene Therapy volume 13, pages 986–990 (2006)Cite this article

Abstract

Replicating, tumor selective viruses are being tested as potential treatments for human cancers. Hypoxia is a pathophysiological cancer condition that alters the lytic potential of the replication-competent adenovirus serotype 5 (Ad5) virus by a mechanism independent of receptor levels or internalization rates. We extend these initial studies to examine the potential effects of hypoxia on the group B adenoviruses (Ads), adenovirus type 3 (Ad3) (group B1) and adenovirus type 11p (Ad11p) (group B2). Receptor expression (CD46) is not altered by hypoxia. However, the lytic potential is compromised in a cell-dependent fashion. Consequently, our study suggests that group B replicating Ad-based treatments, like the group C Ad-5-based viruses, will need to be modified in order to effectively treat hypoxic components of human tumors.

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References

  1. Clark KR, Johnson PR . Gene delivery of vaccines for infectious disease. Curr Opin Mol Ther 2001; 3: 375–384.

    CAS  PubMed  Google Scholar 

  2. Horowitz J . Adenovirus-mediated p53 gene therapy: overview of preclinical studies and potential clinical applications. Curr Opin Mol Ther 1999; 1: 500–509.

    CAS  PubMed  Google Scholar 

  3. Wu Q, Moyana T, Xiang J . Cancer gene therapy by adenovirus-mediated gene transfer. Curr Gene Ther 2001; 1: 101–122.

    Article  CAS  PubMed  Google Scholar 

  4. Dobbelstein M . Replicating adenoviruses in cancer therapy. Curr Top Microbiol Immunol 2004; 273: 291–334.

    CAS  PubMed  Google Scholar 

  5. Kirn D . Replication-selective oncolytic adenoviruses: virotherapy aimed at genetic targets in cancer. Oncogene 2000; 19: 6660–6669.

    Article  CAS  PubMed  Google Scholar 

  6. Molnar-Kimber KL, Sterman DH, Chang M, Kang EH, EIBash M, Lanuti M et al. Impact of preexisting and induced humoral and cellular immune responses in an adenovirus-based gene therapy phase I clinical trial for localized mesothelioma. Hum Gene Ther 1998; 9: 2121–2133.

    Article  CAS  PubMed  Google Scholar 

  7. Nwanegbo E, Vardas E, Gao W, Whittle H, Sun H, Rowe D et al. Prevalence of neutralizing antibodies to adenoviral serotypes 5 and 35 in the adult populations of The Gambia, South Africa, and the United States. Clin Diagn Lab Immunol 2004; 11: 351–357.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Mack CA, Song WR, Carpenter H, Wickham TJ, Kovesdi I, Harvey BG et al. Circumvention of anti-adenovirus neutralizing immunity by administration of an adenoviral vector of an alternate serotype. Hum Gene Ther 1997; 8: 99–109.

    Article  CAS  PubMed  Google Scholar 

  9. Jee YS, Lee SG, Lee JC, Kim MJ, Lee JJ, Kim DY et al. Reduced expression of coxsackievirus and adenovirus receptor (CAR) in tumor tissue compared to normal epithelium in head and neck squamous cell carcinoma patients. Anticancer Res 2002; 22: 2629–2634.

    CAS  PubMed  Google Scholar 

  10. Rauen KA, Sudilovsky D, Le JL, Chew KL, Hann B, Weinberg V et al. Expression of the coxsackie adenovirus receptor in normal prostate and in primary and metastatic prostate carcinoma: potential relevance to gene therapy. Cancer Res 2002; 62: 3812–3818.

    CAS  PubMed  Google Scholar 

  11. Zeimet AG, Muller-Holzner E, Schuler A, Hartung G, Berger J, Hermann M et al. Determination of molecules regulating gene delivery using adenoviral vectors in ovarian carcinomas. Gene Therapy 2002; 9: 1093–1100.

    Article  CAS  PubMed  Google Scholar 

  12. Turturro F . Recombinant adenovirus-mediated cytotoxic gene therapy of lymphoproliferative disorders: is CAR important for the vector to ride? Gene Therapy 2003; 10: 100–104.

    Article  CAS  PubMed  Google Scholar 

  13. You Z, Fischer DC, Tong X, Hasenburg A, Aguilar-Cordova E, Kieback DG . Coxsackievirus-adenovirus receptor expression in ovarian cancer cell lines is associated with increased adenovirus transduction efficiency and transgene expression. Cancer Gene Ther 2001; 8: 168–175.

    Article  CAS  PubMed  Google Scholar 

  14. Holterman L, Vogels R, van der Vlugt R, Sieuwerts M, Grimbergen J, Kaspers J et al. Novel replication-incompetent vector derived from adenovirus type 11 (Ad11) for vaccination and gene therapy: low seroprevalence and non-cross-reactivity with Ad5. J Virol 2004; 78: 13207–13215.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Seshidhar Reddy P, Ganesh S, Limbach MP, Brann T, Pinkstaff A, Kaloss M et al. Development of adenovirus serotype 35 as a gene transfer vector. Virology 2003; 311: 384–393.

    Article  CAS  PubMed  Google Scholar 

  16. Nilsson M, Ljungberg J, Richter J, Kiefer T, Magnusson M, Lieber A et al. Development of an adenoviral vector system with adenovirus serotype 35 tropism; efficient transient gene transfer into primary malignant hematopoietic cells. J Gene Med 2004; 6: 631–641.

    Article  CAS  PubMed  Google Scholar 

  17. Gao W, Robbins PD, Gambotto A . Human adenovirus type 35: nucleotide sequence and vector development. Gene Therapy 2003; 10: 1941–1949.

    Article  CAS  PubMed  Google Scholar 

  18. Vogels R, Zuijdgeest D, van Rijnsoever R, Hartkoorn E, Damen I, de Bethune MP et al. Replication-deficient human adenovirus type 35 vectors for gene transfer and vaccination: efficient human cell infection and bypass of preexisting adenovirus immunity. J Virol 2003; 77: 8263–8271.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Sakurai F, Mizuguchi H, Yamaguchi T, Hayakawa T . Characterization of in vitro and in vivo gene transfer properties of adenovirus serotype 35 vector. Mol Ther 2003; 8: 813–821.

    Article  CAS  PubMed  Google Scholar 

  20. Roelvink PW, Lisonova A, Lee JG, Li Y, Bergelson JM, Finberg RW et al. The coxsackievirus-adenovirus receptor protein can function as a cellular attachment protein for adenovirus serotypes from subgroups A, C, D, E, and F. J Virol 1998; 72: 7909–7915.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Mei YF, Lindman K, Wadell G . Two closely related adenovirus genome types with kidney or respiratory tract tropism differ in their binding to epithelial cells of various origins. Virology 1998; 240: 254–266.

    Article  CAS  PubMed  Google Scholar 

  22. Shayakhmetov DM, Papayannopoulou T, Stamatoyannopoulos G, Lieber A . Efficient gene transfer into human CD34(+) cells by a retargeted adenovirus vector. J Virol 2000; 74: 2567–2583.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Sirena D, Lilienfeld B, Eisenhut M, Kalin S, Boucke K, Beerli RR et al. The human membrane cofactor CD46 is a receptor for species B adenovirus serotype 3. J Virol 2004; 78: 4454–4462.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Segerman A, Atkinson JP, Marttila M, Dennerquist V, Wadell G, Arnberg N . Adenovirus type 11 uses CD46 as a cellular receptor. J Virol 2003; 77: 9183–9191.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Fishelson Z, Donin N, Zell S, Schultz S, Kirschfink M . Obstacles to cancer immunotherapy: expression of membrane complement regulatory proteins (mCRPs) in tumors. Mol Immunol 2003; 40: 109–123.

    Article  CAS  PubMed  Google Scholar 

  26. Pipiya T, Sauthoff H, Huang YQ, Chang B, Cheng J, Heitner S et al. Hypoxia reduces adenoviral replication in cancer cells by downregulation of viral protein expression. Gene Therapy 2005; 12: 911–917.

    Article  CAS  PubMed  Google Scholar 

  27. Shen BH, Hermiston TW . Effect of hypoxia on Ad5 infection, trans gene expression and replication. Gene Therapy 2005; 12: 902–910.

    Article  CAS  PubMed  Google Scholar 

  28. Segerman A, Arnberg N, Erikson A, Lindman K, Wadell G . There are two different species B adenovirus receptors: sBAR, common to species B1 and B2 adenoviruses, and sB2AR, exclusively used by species B2 adenoviruses. J Virol 2003; 77: 1157–1162.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Shayakhmetov DM, Eberly AM, Li ZY, Lieber A . Deletion of penton RGD motifs affects the efficiency of both the internalization and the endosome escape of viral particles containing adenovirus serotype 5 or 35 fiber knobs. J Virol 2005; 79: 1053–1061.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Cho WK, Seong YR, Lee YH, Kim MJ, Hwang KS, Yoo J et al. Oncolytic effects of adenovirus mutant capable of replicating in hypoxic and normoxic regions of solid tumor. Mol Ther 2004; 10: 938–949.

    Article  CAS  PubMed  Google Scholar 

  31. Post DE, Devi NS, Li Z, Brat DJ, Kaur B, Nicholson A et al. Cancer therapy with a replicating oncolytic adenovirus targeting the hypoxic microenvironment of tumors. Clin Cancer Res 2004; 10: 8603–8612.

    Article  CAS  PubMed  Google Scholar 

  32. Post DE, Van Meir EG . A novel hypoxia-inducible factor (HIF) activated oncolytic adenovirus for cancer therapy. Oncogene 2003; 22: 2065–2072.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Sarasijam Deelip Joshi for providing Ad3 and Ad11p; Alan Brooks for Ad11p primers; Rhonda Humm, Jean MacRobbie and Eileen Paulo-Chrisco for providing cell lines; and Richard N Harkins and Gabor Rubanyi for critical reading of the manuscript. This work was supported by a PFO fellowship from Schering AG.

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  1. B H Shen

    Present address: USDA/ARS/WRRC, 800 Buchanan St, Albany, CA, 94710, USA

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  1. Gene Therapy Research Department, Berlex Biosciences, Richmond, CA, USA

    B H Shen, M Bauzon & T W Hermiston

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  1. B H Shen
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  3. T W Hermiston
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Correspondence to T W Hermiston.

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Shen, B., Bauzon, M. & Hermiston, T. The effect of hypoxia on the uptake, replication and lytic potential of group B adenovirus type 3 (Ad3) and type 11p (Ad11p). Gene Ther 13, 986–990 (2006). https://doi.org/10.1038/sj.gt.3302736

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