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:

Inhibition of B16BL6 tumor progression by coadministration of recombinant angiostatin K1-3 and endostatin genes with cationic liposomes

Cancer Gene Therapy volume 11, pages 441–449 (2004)Cite this article

Abstract

Transfection of the antiangiogenic angiostatin and endostatin genes was shown to be an alternative to high-dose administration of angiostatin or endostatin proteins for cancer therapy. We have systematically investigated whether coadministration of the mouse angiostatin kringle 1–3 gene (pFLAG-AngioK1/3) and the endostatin gene (pFLAG-Endo) complexed with cationic liposomes exhibits enhanced therapeutic efficacy. In vitro, the coexpressed mixture of angiostatin K1-3 and endostatin more effectively reduced angiogenesis in chorioallantoic membranes than either angiostatin K1-3 or endostatin alone. In vivo, subcutaneous co-administration of pFLAG-AngioK1/3 and pFLAG-Endo lipoplexes more effectively inhibited vascularization in Matrigel plugs implanted in mice than either one alone. Additionally, subcutaneous administration of these genes inhibited the growth and formation of pulmonary metastases of B16BL6 melanoma cells in mice. Compared to treatment with an empty vector, treatment with pFLAG-AngioK1/3 plus pFLAG-Endo inhibited 81% of tumor growth, while treatment with pFLAG-AngioK1/3 or pFLAG-Endo inhibited tumor growth 70 and 69%, respectively. Cotreatment with the two plasmids after primary tumor excision induced a 90% inhibition of pulmonary metastases versus 79% for pFLAG-AngioK1/3 or 80% for pFLAG-Endo individually. These results suggest that combined administration of angiostatin K1–3 and endostatin genes complexed with cationic liposomes may be an innovated antiangiogenic strategy for cancer therapy.

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
Figure 6

Similar content being viewed by others

References

  1. Folkman J, Shing Y . Angiogenesis. J Biol Chem. 1992;267:10931–10934.

    CAS  PubMed  Google Scholar 

  2. Kim KJ, Li B, Winner J, Gillett N, Phillips HS, Ferrara N . Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumor growth in vivo. Nature. 1993;362:841–844.

    Article  CAS  PubMed  Google Scholar 

  3. Kandel J, Bossy-Wetzel E, Klagsbum M, Folkman J, Hanahan D . Neovascularization is associated with a switch to the export of bFGF in the multistep development of fibrosarcoma. Cell. 1991;66:1095–1104.

    Article  CAS  PubMed  Google Scholar 

  4. O’Relly MS, Holmgren L, Shin Y, et al. Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell. 1994;79:315–328.

    Article  Google Scholar 

  5. Rastinejad F, Polverini PJ, Bouck NP . Regulation of the activity of a new inhibitor of angiogenesis by a cancer suppressor gene. Cell. 1989;56:345–355.

    Article  CAS  PubMed  Google Scholar 

  6. Cao Y, Ji RW, Davidson D, et al. Kringle domains of human angiostatin. J Biol Chem. 1996;271:29461–29467.

    Article  CAS  PubMed  Google Scholar 

  7. O’Reilly MS, Boehm T, Shing Y, et al. Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell. 1997;88:277–285.

    Article  PubMed  Google Scholar 

  8. O’Relly MS, Holmgren L, Shin Y, Chen C, Folkman J . Angiostatin induces and sustains dormancy of human primary tumors in mice. Nat Med. 1996;2:689–692.

    Article  Google Scholar 

  9. Yokoyama Y, Dhanabal M, Griffioen AW, Sukhatme VP, Ramakrishnan S . Synergy between angiostatin and endostatin: inhibition of ovarian cancer growth. Cancer Res. 2000;60:2190–2196.

    CAS  PubMed  Google Scholar 

  10. Boehm T, Folkman J, Browder T, O’Reilly MS . Antiangiogenic therapy of experimental cancer dose not induce acquired drug resistance. Nature. 1997;390:404–407.

    Article  CAS  PubMed  Google Scholar 

  11. Sauter BV, Martinet O, Zhang WJ, Mandeli J, Woo Savio LC . Adenovirus-mediated gene transfer of endostatin in vivo results in high level of transgene expression and inhibition of tumor growth and metastases. Proc Natl Acad Sci USA. 2000;97:4802–4807.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Chen QR, Kumar D, Stass SA, Mixson AJ . Liposome complexed to plasmids encoding angiostatin and endostatin inhibit breast cancer in nude mice. Cancer Res. 1999;59:3308–3312.

    CAS  PubMed  Google Scholar 

  13. Sacco MG, Caniatti M, Cato EM, et al. Liposome-delivered angiostatin strongly inhibits tumor growth and metastatization in a transgenic model of spontaneous breast cancer. Cancer Res. 2000;60:2660–2665.

    CAS  PubMed  Google Scholar 

  14. Sambrook J, Fritsch EF, Maniatis T . Molecular Cloning: a Laboratory Manual. 2nd ed. New York, NY: Cold Spring Harbor Laboratory Press; 1989: 1.31–1.39.

    Google Scholar 

  15. Song YK, Liu F, Liu D . Characterization of cationic liposome-mediated gene transfer in vivo by intravenous administration. Hum Gene Ther. 1997;8:1585–1594.

    Article  CAS  PubMed  Google Scholar 

  16. Barron LG, Meyer KB, Szoka FC . Effects of complement deletion on the pharmacokinetics and gene delivery mediated by cationic lipid–DNA complexes. Hum Gene Ther. 1998;9:315–323.

    Article  CAS  PubMed  Google Scholar 

  17. Templeton NS, Lasic DD, Fredrik PM, Strey HH, Roberts DD, Pavlakis GN . Improved DNA:liposome complex for increased systemic delivery and gene expression. Nat Biotech. 1997;15:647–652.

    Article  CAS  Google Scholar 

  18. Liu F, Song YK, Liu D . Hydrodynamics-based transfection in animals by systemic administration of plasmid DNA. Gene Therapy. 1999;6:1258–1266.

    Article  CAS  PubMed  Google Scholar 

  19. Kang IC, Lee YD, Kim DS . A novel disintegrin salmosin inhibits tumor angiogenesis. Cancer Res. 1999;59:3754–3760.

    CAS  PubMed  Google Scholar 

  20. Passaniti A, Taylor RM, Pili R, et al. A simple, quantitative method for assessing angiogenesis and antiangiogenic agents using reconstituted basement membrane, heparin, and fibroblast growth factor. Lab Invest. 1992;67:519–528.

    CAS  PubMed  Google Scholar 

  21. Weinder N . Intratumoral microvessel density as a prognostic factor in cancer. Am J Pathol. 1995;147:9–19.

    Google Scholar 

  22. Folkman J, Cole P, Zimmerman S . Tumor behavior in isolated perfused organs: in vitro growth and metastases of biopsy material in rabbit thyroid and canine intestinal segment. Ann Surg. 1996;164:491–502.

    Article  Google Scholar 

  23. Fidler IJ, Ellis LM . The implications of angiogenesis for the biology and therapy of cancer metastasis. Cell. 1994;79:185–188.

    Article  CAS  PubMed  Google Scholar 

  24. Weinstar-Saslow D, Steeg PS . Angiogenesis and colonization in the tumor metastatic process: basic and applied advances. FASEB J. 1994;8:401–407.

    Article  Google Scholar 

  25. Pluda JM . Tumor-associated angiogenesis: mechanisms, clinical implication, and therapeutic strategies. Semin Oncol. 1997;24:203–218.

    CAS  PubMed  Google Scholar 

  26. Bicknell R, Harris AL . Anticancer strategies involving the vasculature: vascular targeting and the inhibition of angiogenesis. Semin Cancer Biol. 1992;3:399–407.

    CAS  PubMed  Google Scholar 

  27. Scott PA, Harris AL . Current approaches to targeting cancer using antiangiogenesis therapies. Cancer Treat Rev. 1994;20:393–412.

    Article  CAS  PubMed  Google Scholar 

  28. Fan TP, Jagger R, Bicknell R . Controlling the vasculature: angiogenesis, anti-angiogenesis and vascular targeting of gene therapy. Trends Pharmacol Sci. 1995;16:57–66.

    Article  CAS  PubMed  Google Scholar 

  29. Wen XY, Bai Y, Stewart AK . Adenovirus-mediated human endostatin gene delivery demonstrate strain-specific antitumor activity and acute dose-dependent toxicity in mice. Hum Gene Ther. 2001;12:347–358.

    Article  CAS  PubMed  Google Scholar 

  30. Chesnoy S, Huang L . Enhanced cutaneous gene delivery following intradermal injection of naked DNA in a high ionic strength solution. Mol Ther. 2001;5:57–62.

    Article  Google Scholar 

  31. Dhanabal M, Ramchandran R, Waterman MJ, Knebelmann B, Segal M, Sukhatme VP . Endostatin induces endothelial cell apoptosis. J. Biol. Chem. 1999;274:11721–11726.

    Article  CAS  PubMed  Google Scholar 

  32. Dixelius J, Larsson H, Sasaki T, et al. Endostatin-induced tyrosine kinase signaling through the Shb adaptor protein regulates endothelial cell apoptosis. Blood. 2000;95:3403–3411.

    CAS  PubMed  Google Scholar 

  33. Moser TL, Stack MS, Asplin L, et al. Angiostatin binds ATP synthase on the surface of human endothelial cells. Proc. Natl. Acad. Sci. USA. 1999;96:2811–2816.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Griscelli F, Li H, Bennaceur-Griscelli A, et al. Angiostatin gene transfer: inhibition of tumor growth in vivo by blockage of endothelial cell proliferation associated with a mitosis arrest. Proc Natl Acad Sci USA. 1998;95:6367–6372.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We acknowledge the financial support of the Korea Ministry of Commerce, Industry, and Energy made in the program year of 2002 and the Maeji Academic Research Fund of Yonsei University, 2002.

Author information

Authors and Affiliations

  1. Department of Biomedical Laboratory Science and Institute of Health Science, Yonsei University, Wonju, 220-710, Republic of Korea

    Keun Sik Kim, Hong Sung Kim & Yong Serk Park

  2. Department of Genetic Engineering, Hallym University, Chunchon, 200-702, Republic of Korea

    Jin Seu Park

  3. Department of Biochemistry, Yonsei University, Seoul, 120-749, Republic of Korea

    Young Guen Kwon

Authors
  1. Keun Sik Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hong Sung Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jin Seu Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Young Guen Kwon
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yong Serk Park
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yong Serk Park.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kim, K., Kim, H., Park, J. et al. Inhibition of B16BL6 tumor progression by coadministration of recombinant angiostatin K1-3 and endostatin genes with cationic liposomes. Cancer Gene Ther 11, 441–449 (2004). https://doi.org/10.1038/sj.cgt.7700716

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.cgt.7700716

Keywords

This article is cited by

Search

Advanced search

Quick links