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:

Anti-metastatic gene therapy utilizing subcutaneous inoculation of EC-SOD gene transduced autologous fibroblast suppressed lung metastasis of Meth-A cells and 3LL cells in mice

Abstract

We have previously reported that superoxide stimulates the motility of tumor cells and the administration of Cu-Zn superoxide dismutase (SOD) significantly suppresses metastasis. However, ideally, anti-metastatic therapy should be long-lasting, systemically effective and have low toxicity. The half-life of Cu-Zn SOD in plasma is so short that it cannot provide long-lasting effects. Therefore, in this study we have developed a gene therapy in a mouse model utilizing extracellular SOD (EC-SOD), which is the most prevalent SOD isoenzyme in extracellular fluids. We retrovirally transfected fibroblasts (syngeneic) with the EC-SOD gene and established EC-SOD-secreting fibroblasts. Inoculation of EC-SOD-secreting fibroblasts suppressed both artificial and spontaneous metastatic lung nodules in mouse metastasis models. These data indicate the feasibility of anti-metastatic gene therapy utilizing the EC-SOD gene.

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

Similar content being viewed by others

References

  1. Fidler IJ . Critical factors in the biology of human cancer metastasis. Twenty-eighth GHA Clowes memorial award lecture Cancer Res 1990 50: 6130–6138

    CAS  PubMed  Google Scholar 

  2. Liotta LA, Stracke ML . Tumor invasion and metastases: biochemical mechanisms Cancer Treat Res 1988 40: 223–238

    Article  CAS  PubMed  Google Scholar 

  3. Mullen CA . Metabolic suicide genes in gene therapy Pharm Ther 1994 63: 199–207

    Article  CAS  Google Scholar 

  4. Toh Y et al. Overexpression of manganese superoxide dismutase mRNA may correlate with aggressiveness in gastric and colorectal adenocarcinomas Int J Oncol 2000 17: 107–112

    CAS  PubMed  Google Scholar 

  5. Malafa M et al. MnSOD expression is increased in metastatic gastric cancer J Surg Res 2000 88: 130–134

    Article  CAS  PubMed  Google Scholar 

  6. Van Driel et al. Prognostic estimation of survival of colorectal cancer patients with the quantitative histochemical assay of G6PDH activity and the multiparameter classification program CLASSIF1 Cytometry 1999 38: 176–183

    Article  Google Scholar 

  7. Bittinger F et al. Production of superoxide by human malignant melanoma cells Melanoma Res 1998 8: 381–387

    Article  CAS  PubMed  Google Scholar 

  8. Yoshizaki N et al. Suppressive effect of recombinant human Cu, Zn-superoxide dismutase on lung metastasis of murine tumro cells Int J Cancer 1994 57: 287–292

    Article  CAS  PubMed  Google Scholar 

  9. Anasagasti MJ et al. Sinusoidal endothelium release of hydrogen peroxide enhances very late antigen-4-mediated melanoma cell adherence and tumor cytotoxicity during interleukin-1 promotion of hepatic melanoma metastasis in mice Hepatology 1997 25: 840–846

    Article  CAS  PubMed  Google Scholar 

  10. Fujimiya K, Sugihara K, Nishikawa T . Experimental study on the role of osteoclasts and free radicals in the mandibular invasion of VX2 carcinoma in Japanese white rabbits Bone 1997 20: 245–250

    Article  CAS  PubMed  Google Scholar 

  11. Muramatsu H et al. Superoxide dismutase in SAS human tongue carcinoma cell line is a factor defining invasiveness and cell motility Cancer Res 1995 55: 6210–6214

    CAS  PubMed  Google Scholar 

  12. Tanaka M et al. Suppression of intracellular Cu-Zn SOD results in enhanced motility and metastasis of Meth A sarcoma cells Int J Cancer 1997 73: 187–192

    Article  CAS  PubMed  Google Scholar 

  13. Takenaga M, Igarashi R, Ochiai A, Mizushima Y . Effect of lecithinized superoxide dismutase (PC-SOD) on experimental pulmonary metastasis in mice Free Rad Biol Med 1999 26: 1117–1125

    Article  CAS  PubMed  Google Scholar 

  14. Inoue M, Ebashi I, Watanabe N, Moriono Y . Synthesis of a superoxide dismutase derivative that circulates bound to albumin and accumulates in tissues whose pH is decreased Biochemistry 1989 28: 6619–6624

    Article  CAS  PubMed  Google Scholar 

  15. Kogawa K et al. Enhanced inhibition of experimental metastasis by the combination chemotherapy of Cu-Zn SOD and Adriamycin Clin Exp Metast 1999 17: 239–244

    Article  CAS  Google Scholar 

  16. Marklund SL . Human copper-containing superoxide dismutase of high molecular weight Proc Natl Acad Sci USA 1982 79: 634–638

    Article  Google Scholar 

  17. Karlsson K, Marklund SL . Plasma clearance of human extracellular-superoxide dismutase C in rabbits J Clin Invest 1998 82: 762–766

    Article  Google Scholar 

  18. Rosenfeld W et al. Safety and plasma concentrations of bovine superoxide dismutase administered to human premature infants Dev Pharm Ther 1982 5: 151–161

    CAS  Google Scholar 

  19. Saiki I et al. Antimetastatic effects of synthetic polypeptides containing repeated structure of the cell adhesive Arg-Gly-Asp(RGD) and Tyr-Ile-Gly-Ser-Arg(YigSr) sequences Br J Cancer 1989 60: 722–728

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Tokui M et al. Intramuscular injection of expression plasmid DNA via an affective means of long-term systemic delivery of interleukin-5 Biochem Biophys Res Commun 1997 233: 527–531

    Article  CAS  PubMed  Google Scholar 

  21. Namiki Y, Takahashi T, Ohno T . Gene transduction for disseminated intraperitoneal tumor using cationic liposomes containing non-histone chromatin proteins: cationic liposomal gene therapy of carcinomatosa Gene Therapy 1998 5: 240–246

    Article  CAS  PubMed  Google Scholar 

  22. Wakimoto H et al. Efficient retrovirus-mediated cytokine-gene transduction of primary-cultured human glioma cells for tumor vaccination therapy Jpn J Cancer Res 1997 88: 296–305

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Nielsen LL, Maneval DC . p53 tumor suppressor gene therapy for cancer Cancer Gene Ther 1998 5: 52–63

    CAS  PubMed  Google Scholar 

  24. Smith KJ, Skelton H . Immune and gene therapy for melanoma, and the immuno biology of melanoma Int J Dermatol 1999 38: 490–508

    Article  CAS  PubMed  Google Scholar 

  25. Naitoh J, Belledegrun A . Gene therapy-future is here: a buide to the practicing urologist Urology 1998 51: 367–380

    Article  CAS  PubMed  Google Scholar 

  26. Karlsson K, Marklund SL . Extracellular superoxide dismutase in the vascular system of mammals Biochem J 1998 255: 223–228

    Google Scholar 

  27. Adachi T, Marklund SL . Interactions between human extracellular superoxide dismutase C and sulfated polysaccharides J Biol Chem 1989 264: 8537–8541

    CAS  PubMed  Google Scholar 

  28. Fukai T et al. Vascular expression of extracellular dismutase in atherosclerosis J Clin Invest 1998 101: 2101–2111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We wish to thank Mr Kevin Litton for his careful reading of the manuscript.

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tanaka, M., Kogawa, K., Nakamura, K. et al. Anti-metastatic gene therapy utilizing subcutaneous inoculation of EC-SOD gene transduced autologous fibroblast suppressed lung metastasis of Meth-A cells and 3LL cells in mice. Gene Ther 8, 149–156 (2001). https://doi.org/10.1038/sj.gt.3301362

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.gt.3301362

Keywords

This article is cited by

Search

Quick links