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:

Experimental therapy of allogeneic solid tumors induced in athymic mice with suicide gene-transducing replication-competent foamy virus vectors

Cancer Gene Therapy volume 12, pages 947–953 (2005)Cite this article

Abstract

A replication competent foamy virus derived retroviral vector expressing suicide genes has been constructed and characterized in vitro. Here we used vectors expressing the purine nucleoside phosphorylase (FOV-7/pnp), the nitroreductase (FOV-7/ntr), or the thymidine kinase (FOV-7/tk) suicide gene in an in vivo athymic (nude) mice/human glioblastoma tumor model. Gliomas were induced by subcutanous injection of U87 tumor cells. The virus vector was injected when the tumor became visible. Mice with vector virus-injected tumors were treated with the respective prodrug. The treatment resulted in significant inhibition of tumor growth. Surprisingly, in mice with vector virus-injected tumors without prodrug treatment a similar suppression of tumor growth was observed. In 65% (pnp vector), 75% (ntr vector) and 37% (tk vector) of these mice the tumors stopped growing or vanished and the animals remained tumor free for the 25 weeks of the experiment, whereas all mice of the control groups had to be killed because of the tumor growth. In control experiments, the suppression of tumor growth could also be observed when wild-type foamy virus was injected instead of the suicide gene-transducing vectors. Similar results were obtained using the nude mice/G59 human glioblastoma tumor model. In conclusion, the experiments demonstrate an oncolytic activity of foamy virus replication in a nude-mice glioblastoma xenograft tumor model. The analysis of vector virus DNA by PCR revealed that the vector persisted in different organs of the animals irrespective of the use of a prodrug or the elimination of a tumor.

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

Similar content being viewed by others

References

  1. Culver KW, Ram Z, Wallbidge S, Ishii H, Oldfield EH, Blaese RM . In vivo gene transfer with retroviral vector-producer cells for treatment of experimental brain tumors. Science. 1992;256:1550–1552.

    Article  CAS  PubMed  Google Scholar 

  2. Klatzmann D, Valéry CA, Bensimon G, et al. A phase I/II study of herpes simplex virus type I thymidine kinase “suicide” gene therapy for recurrent glioblastoma. Hum Gene Ther. 1998;9:2595–2604.

    CAS  PubMed  Google Scholar 

  3. Ram Z, Culver KW, Oshiro EM, et al. Therapy of malignant brain tumors by intratumoral implantation of retroviral vector-producing cells. Nature Med. 1997;3:1354–1361.

    Article  CAS  PubMed  Google Scholar 

  4. Kirn D, Niculescu-Duvaz I, Hallden G, Springer CJ . The emerging fields of suicide gene therapy and virotherapy. Trends Mol Med. 2002;8:S68–S73.

    Article  CAS  PubMed  Google Scholar 

  5. Kirn D . Oncolytic virotherapy as a novel treatment platform for cancer. Ernst Schering Res Found Workshop. 2003;43:89–105.

    CAS  Google Scholar 

  6. Chiocca EA . Oncolytic viruses. Nat Rev Cancer. 2002;2:938–950.

    PubMed  Google Scholar 

  7. Solly SK, Trajcevski S, Frisen C, et al. Replicative retroviral vectors for cancer gene therapy. Cancer Gene Ther. 2003;10:30–39.

    Article  CAS  PubMed  Google Scholar 

  8. Rethwilm A . The replication strategy of foamy viruses. Curr Top Microbiol Immunol. 2003;277:1–26.

    CAS  PubMed  Google Scholar 

  9. Falcone V, Schweizer M, Neumann-Haefelin D . Replication of primate foamy viruses in natural and experimental hosts. Curr Top Microbiol Immunol. 2003;277:161–180.

    CAS  PubMed  Google Scholar 

  10. Lindemann D, Heinkelein M, Rethwilm A . Aspects of foamy virus vectors: host range and replication-competent vectors. In: Cid-Arregui A, García-Carrancá A eds. Viral Vecotrs Basic Science and Gene Therapy. Natick, MA: Eaton Publishing; 2000: 515–522.

    Google Scholar 

  11. Trobridge G, Russell DW . Cell cycle requirements for transduction by foamy virus vectors compared to those of oncovirus and lentivirus vectors. J Virol. 2004;78:2327–2335.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Bieniasz PD, Weiss RA, McClure MO . Cell cycle dependence of foamy retrovirus infection. J Virol. 1995;69:7295–7299.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Heneine W, Schweizer M, Sandstrom P, Folks T . Human infection with foamy viruses. Curr Top Microbiol Immunol. 2003;277:181–196.

    CAS  PubMed  Google Scholar 

  14. Epstein MA . Simian retroviral infections in human beings. The Lancet (Correspondence). 2004;364:137–140.

    Google Scholar 

  15. Schmidt M, Herchenröder O, Heeney J, Rethwilm A . Long terminal repeat U3 length polymorphism of human foamy virus. Virology. 1997;230:167–178.

    Article  CAS  PubMed  Google Scholar 

  16. Baunach G, Maurer B, Hahn H, Kranz M, Rethwilm A . Functional analysis of human foamy virus accessory reading frames. J Virol. 1993;67:5411–5418.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Schmidt M, Rethwilm A . Replicating foamy virus-based vectors directing high level expression of foreign genes. Virology. 1995;210:167–178.

    Article  CAS  PubMed  Google Scholar 

  18. Nestler U, Heinkelein M, Lücke M, et al. Foamy virus vectors for suicide gene therapy. Gene Ther. 1997;4:1270–1277.

    Article  CAS  PubMed  Google Scholar 

  19. Sambrook J, Russell DW . Molecular Cloning: a Laboratory Manual. 3rd edn. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press; 2001.

    Google Scholar 

  20. Ausubel FM, Brent R, Kingston RE, et al. Current Protocols in Molecular Biology. New York, NY: John Wiley; 1987.

    Google Scholar 

  21. Bigner DD, Bigner SH, Ponten J, et al. Heterogeneity of Genotypic and phenotypic characteristics of fifteen permanent cell lines derived from human gliomas. J Neuropathol Exp Neurol. 1981;40:201–229.

    Article  CAS  PubMed  Google Scholar 

  22. Westphal M, Hansel M, Hamel W, Kunzmann R, Holzel F . Karyotype analyses of 20 human glioma cell lines. Acta Neurochir. 1994;126:17–26.

    Article  CAS  PubMed  Google Scholar 

  23. Montgomery JA, Hewson K . Analogs of 6-methyl-9-beta-D-ribofuranosylpurine. J Med Chem. 1968;11:48–52.

    Article  CAS  PubMed  Google Scholar 

  24. Schmidt M, Niewiesk S, Heeney J, Aguzzi A, Rethwilm A . Mouse model to study the replication of primate foamy viruses. J Gen Virol. 1997;78:1929–1933.

    Article  CAS  PubMed  Google Scholar 

  25. Ryan MD, Drew J . Foot-and-mouth disease virus 2A oligopeptide mediated cleavage of an artificial polyprotein. EMBO J. 1994;13:928–933.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Rethwilm A . Foamy Viruses. In: Mahy B, ter Meulen V, eds. Topley and Wilson's Microbiology and Microbial Infections. 10th edn, Virology, London: Arnold; 2005.

    Google Scholar 

  27. Switzer WM, Bhullar V, Shanmugam V, et al. Frequent simian foamy virus infection in persons occupationally exposed to nonhuman primates. J Virol. 2004;78:2780–2789.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Wolfe ND, Switzer WM, Carr JK, et al. Naturally acquired simian retrovirus infections in central African hunters. Lancet. 2004;363:932–937.

    Article  PubMed  Google Scholar 

  29. Hahn BH, Shaw GM, De Cock KM, Sharp PM . AIDS as a zoonosis: scientific and public health implications. AIDS. 2000;287:607–614.

    CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by Grants from the BMBF (01KV9817/0 and BEO31P2152), DFG (SFB479), Bayerische Forschungsstiftung, and EU (BMH4-CT97-2010).

Author information

Authors and Affiliations

  1. Institut für Virologie und Immunbiologie, Universität Würzburg, Germany

    Martin Heinkelein, Ursula Hoffmann, Markus Lücke, Horst Imrich & Axel Rethwilm

  2. Pathologisches Institut, Universität Würzburg, Germany

    Justus G Müller

  3. Klinik und Poliklinik für Neurochirurgie, Universität Leipzig, Germany

    Jürgen Meixensberger

  4. Neurochirurgische Klinik, Universitätskrankenhaus Hamburg-Eppendorf, Germany

    Martin Westphahl

  5. Bayer Leverkusen AG, Pharma Research, Wuppertal, Germany

    Axel Kretschmer

Authors
  1. Martin Heinkelein
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ursula Hoffmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Markus Lücke
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Horst Imrich
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Justus G Müller
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jürgen Meixensberger
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Martin Westphahl
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Axel Kretschmer
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Axel Rethwilm
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Axel Rethwilm.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Heinkelein, M., Hoffmann, U., Lücke, M. et al. Experimental therapy of allogeneic solid tumors induced in athymic mice with suicide gene-transducing replication-competent foamy virus vectors. Cancer Gene Ther 12, 947–953 (2005). https://doi.org/10.1038/sj.cgt.7700855

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.cgt.7700855

Keywords

This article is cited by

Search

Advanced search

Quick links