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Lack of Antitumor Activity of Recombinant Endostatin in a Human Neuroblastoma Xenograft Model

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Abstract

Patients with metastatic neuroblastoma are rarely curable with currently available therapy, and the search for new treatment options, which include the use of inhibitors of tumor angiogenesis, is warranted. Here, we have evaluated the efficacy of one of the most promising natural inhibitors of angiogenesis described to date, endostatin, in a human neuroblastoma xenograft model in nude mice. Murine endostatin cDNA was cloned in a bacterial expression vector, expressed as a polyHis-Endostatin fusion protein and purified on Ni2+-NTA beads. Thein vitro activity of soluble endostatin was confirmed on bovine capillary endothelial cells and human umbilical vein endothelial cells. The human neuroblastoma cell line SKNAS was injected subcutaneously in the flank of nude mice and administration of the recombinant angiogenesis inhibitor started when tumors reached the size of 100 μm3. Twenty mg/kg of recombinant precipitated endostatin or PBS was subcutaneously injected daily for 12 days. Serum endostatin levels were measured using a competitive enzyme immunoassay. Tumor growth was only slowed down in endostatin-treated mice when compared to control mice, and no statistically significant difference in serum levels of endostatin was observed between endostatin-treated and control groups. The lack of correlation between serum concentration and tumor response raises concern regarding the mechanism of action of endostatin.

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Authors and Affiliations

  1. Département de Biologie des tumeurs, Centre Léon Bérard, Lyon, France

    Emmanuel Jouanneau, Laurent Alberti, Isabelle Treilleux, Adeline Duc, Valérie Combaret, Marie Favrot & Thomas Bachelot

  2. Faculté de Médecine Rockefeller, CNRS UMR 5578, Lyon, France

    Mimoun Nejjari

  3. INSERM 244, Grenoble, France

    Isabelle Vilgrain

  4. Division of Health Sciences & Technology, Massachusetts Institute of Technology, Cambridge, MA, USA

    Philippe Leboulch

  5. Division of Hematology, Department of Medicine, Brigham & Women's Hospital, Harvard Medical School and, Boston, MA, USA

    Philippe Leboulch

Authors
  1. Emmanuel Jouanneau

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  2. Laurent Alberti

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  3. Mimoun Nejjari

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  4. Isabelle Treilleux

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  5. Isabelle Vilgrain

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  6. Adeline Duc

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  7. Valérie Combaret

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  8. Marie Favrot

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  9. Philippe Leboulch

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  10. Thomas Bachelot

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