Systemic inhibition of tumor growth and tumor metastases by intramuscular administration of the endostatin gene

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.

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Figure 1: In vitro expression of biologically active endostatin.
Figure 2: Serum level of endostatin after intramuscular administration of formulated mouse endostatin expression plasmid.
Figure 3: Inhibition of subcutaneous and lung tumors by intramuscular administration of formulated endostatin plasmid.
Figure 4: Inhibition of tumor vasularization and systemic angiogenesis by intramuscular administration of an endostatin gene medicine.
Figure 5: Effect of DNA dose on tumor growth by intramuscular administration of formulated endostatin plasmid.

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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.

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Correspondence to Wang Min.

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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

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