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:

Eradication of hepatocellular carcinoma xenografts by radiolabelled, lipiodol-inducible gene therapy

Abstract

The promoter region of the early-growth response-1(Egr-1) gene has been shown to be activated by external radiation, thus making a selective tumoricidal effect possible. A previous experiment showed that the Egr-1 promoter can be activated by internal radiation using radioisotopes as well as external radiation. Internal radiation using I-131 lipiodol (I-131-Lip) has been established as one of the most useful therapeutic strategies against hepatoma. We herein linked the Egr-1 promoter to the herpes simplex virus-thymidine kinase (HSV-TK) gene, and investigated its efficacy in hepatoma gene therapy in combination with I-131-Lip. A luciferase assay showed the Egr-1-promoter activity to be markedly increased in hepatoma tissue specimens in an I-131-dose-dependent manner, whereas a less than two-fold increase in this activity was observed in other organs. In addition, the radioactivity derived from I-131 was selectively accumulated in the tumor tissue specimens. To examine the efficacy of EgrTK/ganciclovir (GCV) gene therapy in vivo, subcutaneous hepatoma xenografts in nude mice were transfected using a hemagglutinating virus of Japan (HVJ)-liposome vector. Complete tumor regression was observed in all the EgrTK-transfected tumors following combination treatment with I-131-Lip and GCV 42 days after treatment without any side effects (n=8). In contrast, the tumors continued to grow in all control mice (n=10). Furthermore, the serum α-fetoprotein levels decreased in the combination therapy group, while they increased in the controls. In conclusion, these data indicate that Egr-1 promoter-based gene therapy combined with internal radiation has a selective effect on hepatoma tumors while also showing an improved in vivo efficacy. This combination therapy might, therefore, be an effective human hepatoma gene therapy, even in advanced multiple cases.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  1. Askari F, Wilson J . Provocative gene therapy strategy for the treatment of hepatocellular carcinoma. Hepatology 1992; 16: 273–274.

    Article  CAS  PubMed  Google Scholar 

  2. Colombo M . Hepatocellular carcinoma. J Hepatol 1992; 15: 225–236.

    Article  CAS  PubMed  Google Scholar 

  3. Caruso M et al. Regression of established macroscopic liver metastases after in situ transduction of a suicide gene. Proc Natl Acad Sci USA 1993; 90: 7024–7028.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Barba D, Hardin J, Sadelain M, Gage FH . Development of anti-tumor immunity following thymidine kinase-mediated killing of experimental brain tumors. Proc Natl Acad Sci USA 1994; 91: 4348–4352.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Chen SH et al. Gene therapy for brain tumors: regression of experimental gliomas by adenovirus-mediated gene transfer in vivo. Proc Natl Acad Sci USA 1994; 91: 3054–3057.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Moolten FL . Tumor chemosensitivity conferred by inserted herpes thymidine kinase genes: paradigm for a prospective cancer control strategy. Cancer Res 1986; 46: 5276–5281.

    CAS  PubMed  Google Scholar 

  7. Moolten FL, Wells JM . Curability of tumors bearing herpes thymidine kinase genes transferred by retroviral vectors. J Natl Cancer Inst 1990; 82: 297–300.

    Article  CAS  PubMed  Google Scholar 

  8. Moolten FL . Drug sensitivity (‘suicide’) genes for selective cancer chemotherapy. Cancer Gene Ther 1994; 1: 279–287.

    CAS  PubMed  Google Scholar 

  9. Freeman SM et al. The ‘bystander effect’: tumor regression when a fraction of the tumor mass is genetically modified. Cancer Res 1993; 53: 5274–5283.

    CAS  PubMed  Google Scholar 

  10. Ido A et al. Gene therapy for hepatoma cells using a retrovirus vector carrying herpes simplex virus thymidine kinase gene under the control of human alpha-fetoprotein gene promoter. Cancer Res 1995; 55: 3105–3109.

    CAS  PubMed  Google Scholar 

  11. Kaneko S et al. Adenovirus-mediated gene therapy of hepatocellular carcinoma using cancer-specific gene expression. Cancer Res 1995; 55: 5283–5287.

    CAS  PubMed  Google Scholar 

  12. Wills KN et al. Gene therapy for hepatocellular carcinoma: chemosensitivity conferred by adenovirus-mediated transfer of the HSV-1 thymidine kinase gene. Cancer Gene Ther 1995; 2: 191–197.

    CAS  PubMed  Google Scholar 

  13. Su H, Chang JC, Xu SM, Kan YW . Selective killing of AFP-positive hepatocellular carcinoma cells by adeno-associated virus transfer of the herpes simplex virus thymidine kinase gene. Hum Gene Ther 1996; 7: 463–470.

    Article  CAS  PubMed  Google Scholar 

  14. Kanai F et al. Gene therapy for alpha-fetoprotein-producing human hepatoma cells by adenovirus-mediated transfer of the herpes simplex virus thymidine kinase gene. Hepatology 1996; 23: 1359–1368.

    CAS  PubMed  Google Scholar 

  15. Ohguchi S et al. Expression of alpha-fetoprotein and albumin genes in human hepatocellular carcinomas: limitations in the application of the genes for targeting human hepatocellular carcinoma in gene therapy. Hepatology 1998; 27: 599–607.

    Article  CAS  PubMed  Google Scholar 

  16. Hallahan DE et al. Spatial and temporal control of gene therapy using ionizing radiation. Nat Med 1995; 1: 786–791.

    Article  CAS  PubMed  Google Scholar 

  17. Kawashita Y et al. Regression of hepatocellular carcinoma in vitro and in vivo by radiosensitizing suicide gene therapy under the inducible and spatial control of radiation. Hum Gene Ther 1999; 10: 1509–1519.

    Article  CAS  PubMed  Google Scholar 

  18. Takahashi T, Namiki Y, Ohno T . Induction of the suicide HSV-TK gene by activation of the Egr-1 promoter with radioisotopes. Hum Gene Ther 1997; 8: 827–833.

    Article  CAS  PubMed  Google Scholar 

  19. Bretagne JF et al. Hepatic artery injection of I-131-labeled lipiodol. Part II. Preliminary results of therapeutic use in patients with hepatocellular carcinoma and liver metastases. Radiology 1988; 168: 547–550.

    Article  CAS  PubMed  Google Scholar 

  20. Raoul JL et al. Hepatic artery injection of I-131-labeled lipiodol. Part I. Biodistribution study results in patients with hepatocellular carcinoma and liver metastases. Radiology 1988; 168: 541–545.

    Article  CAS  PubMed  Google Scholar 

  21. Raoul JL et al. Preoperative treatment of hepatocellular carcinoma with intra-arterial injection of 131I-labelled lipiodol. Br J Surg 2003; 90: 1379–1383.

    Article  CAS  PubMed  Google Scholar 

  22. Boucher E et al. Adjuvant intra-arterial injection of iodine-131-labeled lipiodol after resection of hepatocellular carcinoma. Hepatology 2003; 38: 1237–1241.

    Article  CAS  PubMed  Google Scholar 

  23. Glover D, Little JB, Lavin MF, Gueven N . Low dose ionizing radiation-induced activation of connexin 43 expression. Int J Radiat Biol 2003; 79: 955–964.

    Article  CAS  PubMed  Google Scholar 

  24. Nakakuma K et al. Studies on anticancer treatment with an oily anticancer drug injected into the ligated feeding hepatic artery for liver cancer. Cancer 1983; 52: 2193–2200.

    Article  CAS  PubMed  Google Scholar 

  25. Iwai K, Maeda H, Konno T . Use of oily contrast medium for selective drug targeting to tumor: enhanced therapeutic effect and X-ray image. Cancer Res 1984; 44: 2115–2121.

    CAS  PubMed  Google Scholar 

  26. Kanematsu T et al. Selective effects of lipiodolized antitumor agents. J Surg Oncol 1984; 25: 218–226.

    Article  CAS  PubMed  Google Scholar 

  27. Madsen MT, Park CH, Thakur ML . Dosimetry of iodine-131 ethiodol in the treatment of hepatoma. J Nucl Med 1988; 29: 1038–1044.

    CAS  PubMed  Google Scholar 

  28. Chou FI, Lui WY, Chi CW, Chan WK . I-131-lipiodol cytotoxicity in hepatoma cells. Proc Natl Sci Counc Repub China B 1994; 18: 154–160.

    CAS  PubMed  Google Scholar 

  29. Park CH et al. Evaluation of intrahepatic I-131 ethiodol on a patient with hepatocellular carcinoma. Therapeutic feasibility study. Clin Nucl Med 1986; 11: 514–517.

    Article  CAS  PubMed  Google Scholar 

  30. Kajiya Y, Kobayashi H, Nakajo M . Transarterial internal radiation therapy with I-131 lipiodol for multifocal hepatocellular carcinoma: immediate and long-term results. Cardiovasc Intervent Radiol 1993; 16: 150–157.

    Article  CAS  PubMed  Google Scholar 

  31. Raoul JI et al. Internal radiation therapy for hepatocellular carcinoma. Results of a French multicenter phase II trial of transarterial injection of iodine 131-labeled Lipiodol. Cancer 1992; 69: 346–352.

    Article  CAS  PubMed  Google Scholar 

  32. Partensky C et al. Intra-arterial iodine 131-labeled lipiodol as adjuvant therapy after curative liver resection for hepatocellular carcinoma: a phase 2 clinical study. Arch Surg 2000; 135: 1298–1300.

    Article  CAS  PubMed  Google Scholar 

  33. Buscombe JR . Interventional nuclear medicine in hepatocellular carcinoma and other tumours. Nucl Med Commun 2002; 23: 837–841.

    Article  CAS  PubMed  Google Scholar 

  34. Lau WY et al. Adjuvant intra-arterial iodine-131-labelled lipiodol for resectable hepatocellular carcinoma: a prospective randomised trial. Lancet 1999; 353: 797–801.

    Article  CAS  PubMed  Google Scholar 

  35. Abdulkadir SA et al. Impaired prostate tumorigenesis in Egr1-deficient mice. Nat Med 2001; 7: 101–107.

    Article  CAS  PubMed  Google Scholar 

  36. Raper SE et al. Fatal systemic inflammatory response syndrome in a ornithine transcarbamylase deficient patient following adenoviral gene transfer. Mol Genet Metab 2003; 80: 148–158.

    Article  CAS  PubMed  Google Scholar 

  37. Morishita R et al. Novel in vitro gene transfer method for study of local modulators in vascular smooth muscle cells. Hypertension 1993; 21: 894–899.

    Article  CAS  PubMed  Google Scholar 

  38. Kato K et al. Expression of hepatitis B virus surface antigen in adult rat liver. Co-introduction of DNA and nuclear protein by a simplified liposome method. J Biol Chem 1991; 266: 3361–3364.

    CAS  PubMed  Google Scholar 

  39. Hirano T et al. Persistent gene expression in rat liver in vivo by repetitive transfections using HVJ-liposome. Gene Therapy 1998; 5: 459–464.

    Article  CAS  PubMed  Google Scholar 

  40. Seung LP et al. Genetic radiotherapy overcomes tumor resistance to cytotoxic agents. Cancer Res 1995; 55: 5561–5565.

    CAS  PubMed  Google Scholar 

  41. Ho S, Lau WY, Leung TW, Johnson PJ . Internal radiation therapy for patients with primary or metastatic hepatic cancer: a review. Cancer 1998; 83: 1894–1907.

    Article  CAS  PubMed  Google Scholar 

  42. Bellet DH, Wands JR, Isselbacher KJ, Bohuon C . Serum alpha-fetoprotein levels in human disease: perspective from a highly specific monoclonal radioimmunoassay. Proc Natl Acad Sci USA 1984; 81: 3869–3873.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kawashita, Y., Ohtsuru, A., Miki, F. et al. Eradication of hepatocellular carcinoma xenografts by radiolabelled, lipiodol-inducible gene therapy. Gene Ther 12, 1633–1639 (2005). https://doi.org/10.1038/sj.gt.3302531

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.gt.3302531

Keywords

This article is cited by

Search

Quick links