Abstract
Tumors require ongoing angiogenesis to support their growth. Inhibition of angiogenesis by production of angiostatic factors should be a viable approach for cancer gene therapy. Endostatin, a potent angiostatic factor, was expressed in mouse muscle and secreted into the bloodstream for up to 2 weeks after a single intramuscular administration of the endostatin gene. The biological activity of the expressed endostatin was demonstrated by its ability to inhibit systemic angiogenesis. Moreover, the sustained production of endostatin by intramuscular gene therapy inhibited both the growth of primary tumors and the development of metastatic lesions. These results demonstrate the potential utility of intramuscular delivery of an antiangiogenic gene for treatment of disseminated cancers.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Sugarbaker, E.V., Thornthwaite, J. & Ketcham,, A.S. in Progress in Cancer Research and Therapy (eds Day, S.B., Myers, W.P.L., Stansly, P., Garattini, S. & Lewis, M.G.) 227–240 (Raven Press, New York, 1977 ).
Warren, B.A. Chauvin, W.J. & Philips, J. in Progress in Cancer Research and Therapy (eds Day, S.B., Myers, W.P.L., Stansly, P., Garattini, S. & Lewis, M.G.) 185–197 (Raven Press, New York, 1977 ).
Clark, W.H.J. Model predicting survival in stage I melanoma based on tumor progression. J. Natl. Cancer Inst. 81, 1893– 1904 (1989).
Prehn, R.T. The inhibition of tumor growth by tumor mass. Cancer Res. 51, 2–4 (1991).
Prehn, R.T. Two competing influences that may explain concomitant tumor resistance. Cancer Res. 53, 3266–3269 (1993).
O'Reilly, M.S. et al. The suppression of tumor metastases by a primary tumor. Surg. Forum 44, 474–478 (1993).
O'Reilly, M.S. et al. Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell 79, 315–328 (1994).
O'Reilly, M.S. et al. Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell 88, 277–285 (1997).
Volpert, O.V., Lawler, J. & Bouck, N.P. A human fibrosarcoma inhibits systemic angiogenesis and the growth of experimental metastases via thrombospondin-1. Proc. Natl. Acad. Sci. USA 95, 6343–6348 (1998).
Holmgren, L., O'Reilly, M.S. & Folkman, J. Dormancy of micrometastases: balanced proliferation and apoptosis in the presence of angiogenesis suppression. Nat. Med. 1, 149–153 ( 1995).
O'Reilly, M.S., Holmgren, L., Chen, C., & Folkman, J. Angiostatin induces and sustains dormancy of human primary tumors in mice. Nat. Med . 2, 689–692 ( 1996).
Lannutti, B.J., Gately, S.T., Quevedo, M.E., Soff, G.A., & Paller, A.S. Human angiostatin inhibits murine hemangioendothelioma tumor growth in vivo. Cancer Res. 57, 5277–5280 (1997).
Sim, B.K. et al. A recombinant human angiostatin protein inhibits experimental primary and metastatic cancer. Cancer Res. 57, 1329– 1334 (1997).
Boehm, T., Folkman, J., Browder, T. & O'Reilly, M.S. Antiangiogenic therapy of experimental cancer does not induce acquired drug resistance. Nature 390, 404–407 ( 1997).
Folkman, J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat. Med. 1, 27–31 ( 1997).
Hanahan, D. & Folkman, J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86, 353–364 (1996).
Wolff, J.A. et al. Direct gene transfer into mouse muscle in vivo. Science 247, 1465–1468 ( 1990).
Davis, H.L., Demeneix, B.A., Quantin, B., Coulombe, J. & Whalen, R.G. Plasmid DNA is superior to viral vectors for direct gene transfer into adult mouse skeletal muscle. Hum. Gene Ther. 4, 733–740 (1993).
Schofield, J.P. & Caskey, C.T. Non-viral approaches to gene therapy. Br. Med. Bull. 51, 56– 71 (1995).
Aihara, H. & Miyazaki, J. Gene transfer into muscle by electroporation in. Nat. Biotechnol. 16, 867– 870 (1998).
Alila, H. et al. A. Expression of biologically active human insulin-like growth factor-I following intramuscular injection of a formulated plasmid in rats. Hum. Gene Ther. 8, 1785–1795 ( 1997).
Anwer, K. et al. Systemic effect of human growth hormone after intramuscular injection of a single dose of a muscle-specific gene medicine. Hum. Gene Ther . 9, 659–670 ( 1998).
Mumper, R.J. et al. Polyvinyl derivatives as novel interactive polymers for controlled gene delivery to muscle. Pharm. Res. 13, 701–709 (1996).
Mumper, R.J. et al. Protective interactive noncondensing (PINC) polymers for enhanced plasmid distribution and expression in rat skeletal muscle. J Controlled Release 52, 191–203 ( 1998).
Weidner, N., Semple, J.P., Welch, W.R. & Folkman, J. Tumor angiogenesis and metastasis—correlation in invasive breast carcinoma. N. Engl. J. Med. 324, 1– 8 (1991).
Kenyon, B.M. et al. A model of angiogenesis in the mouse cornea. Invest. Ophthalmol. Vis. Sci. 37, 1625–1632 (1996).
Kerbel, R.S. A cancer therapy resistant to resistance. Nature 390 , 335–336 (1997).
Hanahan, D. A flanking attack on cancer. Nat. Med. 4, 13–14 (1998).
Folkman, J. Antiangiogenic gene therapy. Proc. Natl. Acad. Sci. USA 95, 9064–9066 (1998).
Tanaka, T., Cao, Y., Folkman, J. & Fine, H.A. Viral vector-targeted antiangiogenic gene therapy utilizing an angiostatin complementary DNA. Cancer Res. 58, 3362–3369 (1998).
Griscelli, F. 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 95, 6367– 6372 (1998).
Kong, H.L. & Crystal, R.G. Gene therapy strategies for tumor antiangiogenesis. J. Natl. Cancer Inst. 90, 273–286 (1998).
Kong, H.L. et al. Regional suppression of tumor growth by in vivo transfer of a cDNA encoding a secreted form of the extracellular domain of the flt-1 vascular endothelial growth factor receptor. Hum. Gene Ther. 9, 823–833 (1998).
Lin, P. et al. Antiangiogenic gene therapy targeting the endothelium-specific receptor tyrosine kinase Tie2. Proc. Natl. Acad. Sci. USA 95, 8829–8834 (1998).
Li, H. et al. Adenovirus-mediated delivery of a uPA/uPAR antagonist suppresses angiogenesis-dependent tumor growth and dissemination in mice. Gene Ther. 5, 1105–1113 (1998).
Anderson, W.F. Human gene therapy. Nature 392, 25– 30 (1998).
Rolland, A.P. From genes to gene medicines: recent advances in nonviral gene delivery. Crit. Rev. Ther. Drug Carrier Syst. 15, 143– 198 (1998).
Acknowledgements
The authors thank Karel Petrak, Michael Fons, Jeff Nordstrom, Federica Pericle, and Norman Hardman for helpful discussion and critical review of the manuscript; and the Department of Integrated Manufacturing and Quality Control for supplying the plasmids.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Blezinger, P., Wang, J., Gondo, M. et al. Systemic inhibition of tumor growth and tumor metastases by intramuscular administration of the endostatin gene. Nat Biotechnol 17, 343–348 (1999). https://doi.org/10.1038/7895
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/7895
This article is cited by
-
A high risk of osteosarcoma in individuals who are homozygous for the p.D104N in endostatin
Scientific Reports (2015)
-
Impact of p16 status on pro- and anti-angiogenesis factors in head and neck cancers
British Journal of Cancer (2015)
-
Mannan-modified adenovirus targeting TERT and VEGFR-2: A universal tumour vaccine
Scientific Reports (2015)
-
Magnetic resonance-imaging of the effect of targeted antiangiogenic gene delivery in a melanoma tumour model
European Radiology (2015)
-
YLT192, a Novel, Orally Active Bioavailable Inhibitor of VEGFR2 Signaling with Potent Antiangiogenic Activity and Antitumor Efficacy in Preclinical Models
Scientific Reports (2014)
