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:

Adenovirus-mediated tumor-specific combined gene therapy using Herpes simplex virus thymidine/ganciclovir system and murine interleukin-12 induces effective antitumor activity against medullary thyroid carcinoma

Cancer Gene Therapy volume 11, pages 8–15 (2004)Cite this article

Abstract

The present treatment of advanced and metastatic medullary thyroid carcinoma (MTC) is unsatisfactory. Tissue-specific cancer gene therapy is a novel alternative approach. We developed a recombinant adenovirus expressing Herpes simplex type 1 thymidine kinase (HSVtk) driven by a modified CALC-I promoter TCP (AdTCPtk). Infection with this virus showed efficient cytotoxic effect on MTC cell lines (rMTC and TT cells) after treatment with ganciclovir (GCV) in vitro. In a syngenic WAG/Rij rat model, the combination of AdTCPtk/GCV treatment with administration of murine interleukin-12 (mIL-12) expressing adenovirus under control of TCP (AdTCPmIL-12) resulted in effective growth suppression of tumor at the treated site and also at a distant untreated site, in comparison to treatment with AdTCPtk/GCV or AdTCPmIL-12 alone. Moreover, intravenous injection of AdTCPtk, or AdTCPtk+AdTCPmIL-12, followed by administration of GCV, did not cause evident toxicity after administration of GCV. These results indicate that this combined system can provide an effective therapy for metastatic MTC with minimal toxicity.

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. Vitale G, Caraglia M, Ciccarelli A, et al. Current approaches and perspectives in the therapy of medullary thyroid carcinoma. Cancer. 2001;91:1797–1808.

    Article  CAS  PubMed  Google Scholar 

  2. Stone D, David A, Bolognani F, et al. Viral vectors for gene delivery and gene therapy within the endocrine system. J Endocrinol. 2000;164:103–118.

    Article  CAS  PubMed  Google Scholar 

  3. Deonarain MP, Spooner RA, Epenetos AA . Genetic delivery of enzymes for cancer therapy. Gene Therapy. 1995;2:235–244.

    CAS  PubMed  Google Scholar 

  4. Beltinger C, Fulda S, Kammertoens T, et al. Mitochondrial amplification of death signals determines thymidine kinase/ganciclovir-triggered activation of apoptosis. Cancer Res. 2000;60:3212–3217.

    CAS  PubMed  Google Scholar 

  5. Drake RR, Pitlyk K, McMasters RA, et al. Connexin-independent ganciclovir-mediated killing conferred on bystander effect-resistant cell lines by a herpes simplex virus-thymidine kinase-expressing colon cell line. Mol Ther. 2000;2:515–523.

    Article  CAS  PubMed  Google Scholar 

  6. Mesnil M, Piccoli C, Tiraby G, et al. Bystander killing of cancer cells by herpes simplex virus thymidine kinase gene is mediated by connexins. Proc Natl Acad Sci USA. 1996;93:1831–1835.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Mesnil M, Yamasaki H . Bystander effect in herpes simplex virus-thymidine kinase/ganciclovir cancer gene therapy: role of gap-junctional intercellular communication. Cancer Res. 2000;60:3989–3999.

    CAS  PubMed  Google Scholar 

  8. Rodolfo M, Colombo MP . Interleukin-12 as an adjuvant for cancer immunotherapy. Methods. 1999;19:114–120.

    Article  CAS  PubMed  Google Scholar 

  9. Colombo MP, Trinchieri G . Interleukin-12 in anti-tumor immunity and immunotherapy. Cytokine Growth Factor Rev. 2002;13:155–168.

    Article  CAS  PubMed  Google Scholar 

  10. Tang Z, Sun W, Chen S . Combination therapy of murine liver cancer with IL-12 gene and HSV-TK gene. Zhonghua Zhong Liu Za Zhi. 1999;21:332–335.

    CAS  PubMed  Google Scholar 

  11. Drozdzik M, Qian C, Xie X, et al. Combined gene therapy with suicide gene and interleukin-12 is more efficient than therapy with one gene alone in a murine model of hepatocellular carcinoma. J Hepatol. 2000;32:279–286.

    Article  CAS  PubMed  Google Scholar 

  12. Hall SJ, Canfield SE, Yan Y, et al. A novel bystander effect involving tumor cell-derived Fas and FasL interactions following Ad.HSV-tk and Ad.mIL-12 gene therapies in experimental prostate cancer. Gene Therapy. 2002;9:511–517.

    Article  CAS  PubMed  Google Scholar 

  13. Lechanteur C, Delvenne P, Princen F, et al. Combined suicide and cytokine gene therapy for peritoneal carcinomatosis. Gut. 2000;47:343–348.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Nasu Y, Bangma CH, Hull GW, et al. Combination gene therapy with adenoviral vector-mediated HSV-tk+GCV and IL-12 in an orthotopic mouse model for prostate cancer. Prostate Cancer Prostatic Dis. 2001;4:44–55.

    Article  CAS  PubMed  Google Scholar 

  15. Toda M, Martuza RL, Rabkin SD . Combination suicide/cytokine gene therapy as adjuvants to a defective herpes simplex virus-based cancer vaccine. Gene Therapy. 2001;8:332–339.

    Article  CAS  PubMed  Google Scholar 

  16. Lohr F, Huang Q, Hu K, et al. Systemic vector leakage and transgene expression by intratumorally injected recombinant adenovirus vectors. Clin Cancer Res. 2001;7:3625–3628.

    CAS  PubMed  Google Scholar 

  17. Brand K, Arnold W, Bartels T, et al. Liver-associated toxicity of the HSV-tk/GCV approach and adenoviral vectors. Cancer Gene Ther. 1997;4:9–16.

    CAS  PubMed  Google Scholar 

  18. van der Eb MM, Cramer SJ, Vergouwe Y, et al. Severe hepatic dysfunction after adenovirus-mediated transfer of the herpes simplex virus thymidine kinase gene and ganciclovir administration. Gene Therapy. 1998;5:451–458.

    Article  CAS  PubMed  Google Scholar 

  19. Brand K, Loser P, Arnold W, et al. Tumor cell-specific transgene expression prevents liver toxicity of the adeno-HSVtk/GCV approach. Gene Therapy. 1998;5:1363–1371.

    Article  CAS  PubMed  Google Scholar 

  20. Nettelbeck DM, Jerome V, Muller R . Gene therapy: designer promoters for tumour targeting. Trends Genet. 2000;16:174–181.

    Article  CAS  PubMed  Google Scholar 

  21. Minemura K, Takeda T, Nagasawa T, et al. Cell-specific induction of sensitivity to ganciclovir in medullary thyroid carcinoma cells by adenovirus-mediated gene transfer of herpes simplex virus thymidine kinase. Endocrinology. 2000;141:1814–1822.

    Article  CAS  PubMed  Google Scholar 

  22. Yamazaki M, Zhang R, Straus FH, et al. Effective gene therapy for medullary thyroid carcinoma using recombinant adenovirus inducing tumor-specific expression of interleukin-12. Gene Therapy. 2002;9:64–74.

    Article  CAS  PubMed  Google Scholar 

  23. DeGroot LJ, Zhang R . Clinical review 131: gene therapy for thyroid cancer: where do we stand? J Clin Endocrinol Metab. 2001;86:2923–2928.

    Article  CAS  PubMed  Google Scholar 

  24. Peleg S . Modified binding of proteins from calcitonin-negative tumor cells to the neuroendocrine-specific CANNTG motif of the calcitonin gene. Nucleic Acids Res. 1993;21:5360–5365.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Messina M, Yu DM, Learoyd DL, et al. High level, tissue-specific expression of a modified calcitonin/calcitonin gene-related peptide promoter in a human medullary thyroid carcinoma cell line. Mol Cell Endocrinol. 2000;164:219–224.

    Article  CAS  PubMed  Google Scholar 

  26. Russwurm S, Stonans I, Stonane E, et al. Procalcitonin and CGRP-1 mrna expression in various human tissues. Shock. 2001;16:109–112.

    Article  CAS  PubMed  Google Scholar 

  27. Bracq S, Taboulet J, Machairas M, et al. Calcitonin mRNA is produced in liver by two different splicing pathways. Mol Cell Endocrinol. 1997;128:111–115.

    Article  CAS  PubMed  Google Scholar 

  28. Elshami AA, Cook JW, Amin KM, et al. The effect of promoter strength in adenoviral vectors containing herpes simplex virus thymidine kinase on cancer gene therapy in vitro and in vivo. Cancer Gene Ther. 1997;4:213–221.

    CAS  PubMed  Google Scholar 

  29. Beck C, Cayeux S, Lupton SD, et al. The thymidine kinase/ganciclovir-mediated "suicide" effect is variable in different tumor cells. Hum Gene Ther. 1995;6:1525–1530.

    Article  CAS  PubMed  Google Scholar 

  30. Maron A, Havaux N, Le Roux A, et al. Differential toxicity of ganciclovir for rat neurons and astrocytes in primary culture following adenovirus-mediated transfer of the HSVtk gene. Gene Therapy. 1997;4:25–31.

    Article  CAS  PubMed  Google Scholar 

  31. Melcher A, Todryk S, Hardwick N, et al. Tumor immunogenicity is determined by the mechanism of cell death via induction of heat shock protein expression. Nat Med. 1998;4:581–587.

    Article  CAS  PubMed  Google Scholar 

  32. Todryk S, Melcher AA, Hardwick N, et al. Heat shock protein 70 induced during tumor cell killing induces Th1 cytokines and targets immature dendritic cell precursors to enhance antigen uptake. J Immunol. 1999;163:1398–1408.

    CAS  PubMed  Google Scholar 

  33. Vile RG, Castleden S, Marshall J, et al. Generation of an anti-tumour immune response in a non-immunogenic tumour: HSVtk killing in vivo stimulates a mononuclear cell infiltrate and a Th1-like profile of intratumoural cytokine expression. Int J Cancer. 1997;71:267–274.

    Article  CAS  PubMed  Google Scholar 

  34. Soler MN, Milhaud G, Lekmine F, et al. Treatment of medullary thyroid carcinoma by combined expression of suicide and interleukin-2 genes. Cancer Immunol Immunother. 1999;48:91–99.

    Article  CAS  PubMed  Google Scholar 

  35. Green DR, Beere HM . Apoptosis. Gone but not forgotten. Nature. 2000;405:28–29.

    Article  CAS  PubMed  Google Scholar 

  36. Serazin-Leroy V, Denis-Henriot D, Morot M, et al. Semi-quantitative RT-PCR for comparison of mRNAs in cells with different amounts of housekeeping gene transcripts. Mol Cell Probes. 1998;12:283–291.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by a Center of Excellence award from Knoll Pharmaceuticals, and by the David Wiener Research Fund.

Author information

Authors and Affiliations

  1. Department of Medicine, Thyroid Study Unit, The University of Chicago, Chicago, Illinois, USA

    Masanori Yamazaki & Leslie J DeGroot

  2. Department of Pathology, The University of Chicago, Chicago, Illinois, USA

    Francis H Straus

  3. Department of Cancer Genetics, Kolling Institute of Medical Research, Royal North Shore Hospital, St Leonards, NSW, Australia

    Marinella Messina & Bruce G Robinson

  4. Department of Medicine, University of Sydney, Sydney, NSW, Australia

    Bruce G Robinson

  5. Department of Aging Medicine and Geriatrics, Shinshu University School of Medicine, Matsumoto, Japan

    Teiji Takeda & Kiyoshi Hashizume

Authors
  1. Masanori Yamazaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Francis H Straus
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Marinella Messina
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Bruce G Robinson
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Teiji Takeda
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kiyoshi Hashizume
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Leslie J DeGroot
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Leslie J DeGroot.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yamazaki, M., Straus, F., Messina, M. et al. Adenovirus-mediated tumor-specific combined gene therapy using Herpes simplex virus thymidine/ganciclovir system and murine interleukin-12 induces effective antitumor activity against medullary thyroid carcinoma. Cancer Gene Ther 11, 8–15 (2004). https://doi.org/10.1038/sj.cgt.7700636

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.cgt.7700636

Keywords

This article is cited by

Search

Advanced search

Quick links