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:

Heat-inducible TNF-α gene therapy combined with hyperthermia using magnetic nanoparticles as a novel tumor-targeted therapy

Cancer Gene Therapy volume 8, pages 649–654 (2001)Cite this article

Abstract

Heat-induced therapeutic gene expression is highly desired for gene therapy to minimize side effects. Furthermore, if the gene expression is triggered by heat stress, combined therapeutic effects of hyperthermia and gene therapy may be possible. We combined TNF-α gene therapy driven by the stress-inducible promoter, gadd 153, with hyperthermia using magnetite cationic liposomes (MCLs). In nude mice, MCLs induced cell death throughout much of the tumor area on heating under an alternating magnetic field. This heat stress also resulted in a 3-fold increase in TNF-α gene expression driven by the gadd 153 promoter as compared with that of nonheated tumor. TNF-α gene expression was also observed in the peripheral area where the hyperthermic effect was not enough to cause cell death. The combined treatment strongly arrested tumor growth in nude mice over a 30-day period, suggesting potential for cancer treatment. Cancer Gene Therapy (2001) 8, 649–654.

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

Similar content being viewed by others

References

  1. Gerner EW, Hersh EM, Pennington M, et al . Heat-inducible vectors for use in gene therapy Int J Hyperthermia 2000 16: 171–181

    Article  CAS  Google Scholar 

  2. Walther W, Stein U, Fichtner I, et al . mdr1 promoter-driven tumor necrosis factor-α expression for a chemotherapy-controllable combined in vivo gene therapy and chemotherapy of tumors Cancer Gene Ther 2000 7: 893–900

    Article  CAS  Google Scholar 

  3. Manome Y, Kunieda T, Wen PK, et al . Transgene expression in malignant glioma using a replication-defective adenoviral vector containing the EGR-1 promoter: activation by ionizing radiation or uptake of radioactive iododeoxyuridine Hum Gene Ther 1998 9: 1409–1417

    Article  CAS  Google Scholar 

  4. Bellomo G, Perotti M, Taddei F, et al . Tumor necrosis factor α induces apoptosis in mammary adenocarcinoma cells by an increase in intranuclear free Ca2+ concentration and DNA fragmentation Cancer Res 1992 52: 1342–1346

    CAS  PubMed  Google Scholar 

  5. Palladino MA, Shalaby MR, Kramer SM, et al . Characterization of the antitumor activities of human tumor necrosis factor-α and the comparison with other cytokines: induction of tumor specific immunity J Immunol 1987 138: 4023–4032

    CAS  PubMed  Google Scholar 

  6. Spriggs DR, Yates SW . Cancer chemotherapy: experience with TNF administration in humans In: Beutler B, ed. Tumor Necrosis Factors: the Molecules and Their Emerging Roles in Medicine New York: Raven Press 1992 383–406

  7. Kobayashi T . Hyperthermia for brain tumors Jpn J Hyperthermic Oncol 1993 9: 245–249

    Article  Google Scholar 

  8. Raaphorst G, Yang H, Wilkins D, et al . Cisplatin, hyperthermia and radiation treatment in human cisplatin-sensitive and resistant glioma cell lines Int J Hyperthermia 1996 12: 801–812

    Article  CAS  Google Scholar 

  9. Montes H, Hynynen K . A system for the simultaneous delivery of intraoperative radiation and ultrasound hyperthermia Int J Hyperthermia 1995 11: 109–119

    Article  CAS  Google Scholar 

  10. Watanabe N, Niitsu Y, Umeno H, et al . Synergistic cytotoxic and antitumor effects of recombinant human tumor necrosis factor and hyperthermia Cancer Res 1988 48: 650–653

    CAS  PubMed  Google Scholar 

  11. Shinkai M, Matsui M, Kobayashi T . Heat properties of magnetoliposomes for local hyperthermia Jpn J Hyperthermic Oncol 1994 10: 168–177

    Article  Google Scholar 

  12. Shinkai M, Yanase M, Honda H, et al . Intracellular hyperthermia for cancer using magnetite cationic liposomes: in vitro study Jpn J Cancer Res 1996 87: 1179–1183

    Article  CAS  Google Scholar 

  13. Yanase M, Shinkai M, Honda H, et al . Intracellular hyperthermia for cancer using magnetite cationic liposomes: ex vivo study Jpn J Cancer Res 1997 88: 630–632

    Article  CAS  Google Scholar 

  14. Yanase M, Shinkai M, Honda H, et al . Intracellular hyperthermia for cancer using magnetite cationic liposomes: an in vivo study Jpn J Cancer Res 1998 89: 463–469

    Article  CAS  Google Scholar 

  15. Luethy JD, Fargnoli J, Park JS, et al . Isolation and characterization of the hamster gadd153 gene J Biol Chem 1990;2 65: 16521–16526

    Google Scholar 

  16. Luethy JD, Holbrook NK . Activation of the gadd153 promoter by genotoxic agents: a rapid and specific response to DNA damage Cancer Res 1992 52: 5–10

    CAS  PubMed  Google Scholar 

  17. Delmastro DA, Li J, Vaisman A, et al . DNA damage inducible-gene expression following platinum treatment in human ovarian carcinoma cell lines Cancer Chemother Pharmacol 1997 39: 245–253

    CAS  PubMed  Google Scholar 

  18. Ropp M, Courgeon AM, Calvayrac R, et al . The possible role of the superoxide ion in the induction of heat-shock and specific proteins in aerobic Drosophila cells during return to normoxia after a period of anaerobiosis Can J Biochem Cell Biol 1983 61: 456–461

    Article  CAS  Google Scholar 

  19. Ito A, Shinkai M, Bouhon IA, et al . Induction of TNF-α gene expression by heat inducible promoter gadd 153 Jpn J Hyperthermic Oncol 2000 16: 91–98

    Article  Google Scholar 

  20. Ito A, Shinkai M, Bouhon IA, et al . Bystander-killing effect and cyclic induction of TNF-α gene under heat inducible promoter gadd 153 J Biosci Bioeng 2000 90: 437–441

    Article  CAS  Google Scholar 

  21. Yoshida J, Mizuno M, Yagi K . Secretion of human β-interferon into the cystic fluid of glioma transfected with the interferon gene J Clin Biochem Nutr 1991 11: 123–128

    Article  CAS  Google Scholar 

  22. Montgomery D . Design and Analysis of Experiments 3rd edn New York: John Wiley and Sons 1991

    Google Scholar 

  23. Bramson JL, Hitt M, Gauldie J, et al . Pre-existing immunity to adenovirus does not prevent tumor regression following intratumoral administration of a vector expressing IL-12 but inhibits virus dissemination Gene Ther 1997 4: 1069–1076

    Article  CAS  Google Scholar 

  24. Zhang R, Straus FH, DeGroot LJ . Effective genetic therapy of established medullary thyroid carcinomas with murine interleukin-2: dissemination and cytotoxicity studies in a rat tumor model Endocrinology 1999 140: 2152–2158

    Article  CAS  Google Scholar 

  25. Mizuno M, Yoshida J, Sugita K, et al . Growth inhibition of glioma cells transfected with the human β-interferon gene by liposomes coupled with a monoclonal antibody Cancer Res 1990 50: 7826–7829

    CAS  PubMed  Google Scholar 

  26. Le B, Shinkai M, Kitade T, et al . Preparation of tumor-specific magnetoliposomes and their application for hyperthermia J Chem Eng Jpn 2000 33: 821–826

    Google Scholar 

Download references

Acknowledgements

We are grateful to Nikki Holbrook (National Institute on Aging, Baltimore, MD) for providing the JymCAT0 plasmid including the gadd 153 promoter and Hirohumi Hamada (Cancer Chemotherapy Center, Japanese Foundation for Cancer Research) for providing the plasmid SKhTNF-α including the h TNF-α gene.

Author information

Authors and Affiliations

  1. Department of Biotechnology, Graduate School of Engineering, Nagoya University, Nagoya, 464-8603, Japan

    Akira Ito, Masashige Shinkai, Hiroyuki Honda & Takeshi Kobayashi

Authors
  1. Akira Ito
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Masashige Shinkai
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hiroyuki Honda
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Takeshi Kobayashi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Masashige Shinkai.

Additional information

This study was partially funded by a Grant-in-Aid for Scientific Research on Priority Areas (Nos. 10145104 and 11227202) and a Grant-in-Aid for JSPS Fellows (No. 12004238) from the Ministry of Education, Science, Sports and Culture of Japan.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ito, A., Shinkai, M., Honda, H. et al. Heat-inducible TNF-α gene therapy combined with hyperthermia using magnetic nanoparticles as a novel tumor-targeted therapy. Cancer Gene Ther 8, 649–654 (2001). https://doi.org/10.1038/sj.cgt.7700357

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.cgt.7700357

Keywords

This article is cited by

Search

Advanced search

Quick links