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.

  • Research Article
  • Published:

Retrovirus-mediated transfer of prothymosin gene inhibits tumor growth and prolongs survival in murine bladder cancer

Gene Therapy volume 8, pages 1609–1617 (2001)Cite this article

Abstract

To explore the potential use of prothymosin α(ProT), a putative thymic hormone, in gene therapy for bladder cancer, we generated a replication-defective recombinant retroviral vector encoding ProT and tested its antitumor effect on the MBT-2 murine bladder cancer. C3H/HeN mice injected with MBT-2 cells in conjunction with retroviruses encoding ProT exhibited smaller tumor mass, lower tumor incidence and higher survival rate, as well as higher antitumor cytotoxic activities compared with those injected with control viruses. However, such effects were not observed in severe combined immunodeficiency mice, suggesting that ProT exerts antitumor effects through its immunomodulatory activities. Cell growth in monolayer culture and colony formation in soft agar were enhanced in ProT gene-modified MBT-2 clones, and such growth-promoting activities of ProT could be reversed if its nuclear localization signal (NLS) was deleted. To circumvent the proliferation-promoting effect of ProT on tumor cells, a retroviral vector encoding ProT lacking NLS was constructed. Our results showed that retroviruses encoding NLS-deleted ProT was more efficacious than those encoding wild-type ProT in prolonging survival of tumor-bearing mice. This is the first report indicating that ProT, in particular NLS-deleted ProT, delivered by retroviral vectors may be further explored for the treatment of bladder cancer.

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

Similar content being viewed by others

References

  1. Cordero OJ, Maurer HR, Nogueira M . Novel approaches to immunotherapy using thymic peptides Immunol Today 1997 18: 10–13

    Article  CAS  PubMed  Google Scholar 

  2. Haritos AA, Goodall GJ, Horecker BL . Prothymosin α: isolation and properties of the major immunoreactive form of thymosin α1 in rat thymus Proc Natl Acad Sci USA 1984 81: 1008–1011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Haritos AA . Parathymosin α: a peptide from rat tissues with structural homology to prothymosin α Proc Natl Acad Sci USA 1985 82: 1050–1053

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Saito S . Immunotherapy of bladder cancer with cytokine gene-modified tumor vaccines Cancer Res 1994 54: 3516–3520

    CAS  PubMed  Google Scholar 

  5. Connor J . Regression of bladder tumors in mice treated with interleukin gene-modified tumor cells J Exp Med 1993 177: 1127–1134

    Article  CAS  PubMed  Google Scholar 

  6. Pineiro A, Cordero OJ, Nogueira M . Fifteen years of prothymosin alpha: contradictory past and new horizons Peptides 2000 21: 1433–1446

    Article  CAS  PubMed  Google Scholar 

  7. Salvati F . Combined treatment with thymosin-α1 and low-dose interferon-α after ifosfamide in non-small cell lung cancer: a phase-II controlled trial Anticancer Res 1996 16: 1001–1004

    CAS  PubMed  Google Scholar 

  8. Heidecke H, Eckert K, Schulze-Forster K, Maurer HR . Prothymosin α1 effects in vitro on chemotaxis, cytotoxicity and oxidative response of neutrophils from melanoma, colorectal and breast tumor patients Int J Immunopharmacol 1997 19: 413–420

    Article  CAS  PubMed  Google Scholar 

  9. Shiau AL . Prothymosin α enhances protective immune responses induced by oral DNA vaccination against pseudorabies delivered by Salmonella choleraesuis Vaccine 2001 19: 3947–3956

    Article  CAS  PubMed  Google Scholar 

  10. Wu CL, Shiau AL, Lin CS . Prothymosin α promotes cell proliferation in NIH3T3 cells Life Sci 1997 61: 2091–2101

    Article  CAS  PubMed  Google Scholar 

  11. Dominguez F . Tissue concentrations of prothymosin α: a novel proliferation index of primary breast cancer Eur J Cancer 1993 29A: 893–897

    Article  CAS  PubMed  Google Scholar 

  12. Magdalena C, Dominguez F, Loidi L, Puente JL . Tumor prothymosin α content, a potential prognostic marker for primary breast cancer Br J Cancer 2000 82: 584–590

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Sasaki H . Elevated plasma thymosin-α1 levels in lung cancer patients Eur J Cardiothorac Surg 1997 12: 885–891

    Article  CAS  PubMed  Google Scholar 

  14. Manrow RE, Sburlati AR, Hanover JA, Berger SL . Nuclear targeting of prothymosin α J Biol Chem 1991 266: 3916–3924

    CAS  PubMed  Google Scholar 

  15. Evstafieva AG . Prothymosin α fragmentation in apoptosis FEBS Lett 2000 467: 150–154

    Article  CAS  PubMed  Google Scholar 

  16. Low TL, Goldstein AL . Thymosins: structure, function and therapeutic applications Thymus 1984 6: 27–42

    CAS  PubMed  Google Scholar 

  17. Vareli K . Nuclear distribution of prothymosin α and parathymosin: evidence that prothymosin alpha is associated with RNA synthesis processing and parathymosin with early DNA replication Exp Cell Res 2000 257: 152–161

    Article  CAS  PubMed  Google Scholar 

  18. Morales A, Djeu J, Herberman RB . Immunization by irradiated whole cells or cell extracts against an experimental bladder tumor Invest Urol 1980 17: 310–313

    CAS  PubMed  Google Scholar 

  19. Tzai TS . Effect of perioperative chemoimmunotherapy with cyclophosphamide and autologous tumor vaccine in murine MBT-2 bladder cancer J Urol 1994 151: 1680–1686

    Article  CAS  PubMed  Google Scholar 

  20. Kawabata K . A physiological role of interferon (IFN)-β derived from tumor: tumor growth of a mouse bladder carcinoma line MBT-2 is partially suppressed by autocrine IFN-β Cancer Lett 1997 113: 159–164

    Article  CAS  PubMed  Google Scholar 

  21. Kawabata K . A physiological role of interferon (IFN)-β derived from tumor: tumor growth of a mouse bladder carcinoma line MBT-2 is partially suppressed by autocrine IFN-β

  22. Gilboa E . Immunotherapy of cancer with genetically modified tumor vaccines Semin Oncol 1996 23: 101–107

    CAS  PubMed  Google Scholar 

  23. Shiau AL, Lin CY, Tzai TS, Wu CL . Postoperative immuno-gene therapy of murine bladder tumor by in vivo administration of retroviruses expressing mouse interferon-γ Cancer Gene Ther 2001 8: 73–81

    Article  CAS  PubMed  Google Scholar 

  24. Jhappan C . DNA-PKcs: a T-cell tumor suppressor encoded at the mouse scid locus Nat Genet 1997 17: 483–486

    Article  CAS  PubMed  Google Scholar 

  25. Danos O, Mulligan RC . Safe and efficient generation of recombinant retroviruses with amphotropic and ecotropic host ranges Proc Natl Acad Sci USA 1988 85: 6460–6464

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Rayner JR, Gonda TJ . A simple and efficient procedure for generating stable expression libraries by cDNA cloning in a retroviral vector Mol Cell Biol 1994 14: 880–887

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Evstafieva AG . Overproduction in Escherichia coli, purification and properties of human prothymosin α Eur J Biochem 231 1995: 639–643

    Google Scholar 

Download references

Acknowledgements

We are indebted to Dr TJ Gonda (Hanson Center for Cancer Research, Adelaide, Australia) and Dr RC Mulligan (Whitehead Institute for Biomedical Research, Cambridge, MA,USA) for providing pRUFneo plasmid and retroviral packaging cells, respectively. This work was supported by grants from the National Science Council (NSC87-2312-B006-005 and NSC89-2318-B006-007-M51 to CLW and NSC89-2318-B-006-008-M51 to ALS), Taiwan.

Author information

Authors and Affiliations

  1. Department of Microbiology, National Cheng Kung University Medical College, Tainan, Taiwan

    A-L Shiau & P-R Lin

  2. Department of Biochemistry, National Cheng Kung University Medical College, Tainan, Taiwan

    M-Y Chang & C-L Wu

Authors
  1. A-L Shiau
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. P-R Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M-Y Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. C-L Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Shiau, AL., Lin, PR., Chang, MY. et al. Retrovirus-mediated transfer of prothymosin gene inhibits tumor growth and prolongs survival in murine bladder cancer. Gene Ther 8, 1609–1617 (2001). https://doi.org/10.1038/sj.gt.3301568

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.gt.3301568

Keywords

This article is cited by

Search

Advanced search

Quick links