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Evaluation of endostatin antiangiogenesis gene therapy in vitro and in vivo

Cancer Gene Therapy volume 8, pages 982–989 (2001)Cite this article

Abstract

Progressive growth and metastasis of solid tumors require angiogenesis, or the formation of new blood vessels. Endostatin is a 20-kDa carboxy-terminal fragment of collagen XVIII that has been shown to inhibit endothelial cell proliferation and tumor angiogenesis. Replication-deficient recombinant adenovirus (rAd) vectors were constructed, which encoded secreted forms of human and mouse endostatin (HECB and MECB, respectively), and, as a control, human alkaline phosphatase (APCB). Accumulation of endostatin was demonstrated in supernatants of cultured cells infected with the endostatin rAds. These supernatants disrupted tubule formation, inhibited migration and proliferation, and induced apoptosis in human dermal vascular endothelial cells or human vascular endothelial cells. Endostatin-containing supernatants had no effect on the proliferation of MidT2-1 mouse mammary tumor cells in vitro. A pharmacokinetic study of MECB in immunocompetent FVB mice demonstrated a 10-fold increase of serum endostatin concentrations 3 days after intravenous administration of 1×1010 particles of this rAd (215–257 ng/mL compared to 12–38 ng/mL in control rAd-treated mice). Intravenous administration of MECB reduced b-FGF stimulated angiogenesis into Matrigel plugs by 38%. Intratumoral MECB inhibited growth of MidT2-1 syngeneic mammary tumors in FVB mice, but had minimal impact on the growth of MDA-MB-231 human breast tumors in SCID mice. Intravenous therapy with MECB also initially inhibited growth of MidT2-1 tumors, but this activity was subsequently blocked by induced anti-rAd antibodies. In summary, endostatin gene therapy effectively suppressed angiogenic processes in vitro and in vivo in several model systems. Cancer Gene Therapy (2001) 8, 982–989

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Author notes

  1. Loretta L Nielsen

    Present address: Targeted Molecules, 6605 Nancy Ridge Drive, San Diego, 92121, CA, USA

Authors and Affiliations

  1. Canji Inc., San Diego, 92121, California, USA

    Xiaomei Jin, Rob Bookstein, Ken Wills, Jenny Avanzini, Van Tsai & Drake LaFace

  2. Tumor Biology, Schering-Plough Research Institute, Kenilworth, 07033, New Jersey, USA

    Gaby Terracina, Bin Shi & Loretta L Nielsen

Authors
  1. Xiaomei Jin
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  2. Rob Bookstein
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  3. Ken Wills
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  4. Jenny Avanzini
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  6. Drake LaFace
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  7. Gaby Terracina
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Correspondence to Xiaomei Jin.

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Jin, X., Bookstein, R., Wills, K. et al. Evaluation of endostatin antiangiogenesis gene therapy in vitro and in vivo. Cancer Gene Ther 8, 982–989 (2001). https://doi.org/10.1038/sj.cgt.7700396

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