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Endostatin therapy reveals a U-shaped curve for antitumor activity

Cancer Gene Therapy volume 13, pages 619–627 (2006)Cite this article

Abstract

Developing continuous systemic delivery of endostatin has been a goal of many laboratories. We have employed a method of gene therapy utilizing different viral constructs. Here, we report that a new serotype of adeno-associated viruses, which incorporates canine endostatin, provides dose-dependent transgene expression in the circulation after intramuscular injection in mice. Elevated levels of endostatin remained stable in the circulation for at least 4 months. In vitro assays determined that the protein expressed was biologically active. Antitumor activities of the above construct demonstrated a U-shape curve, where the maximum activity was observed within a certain critical concentration range. These data suggest that an optimum dose range may be required to achieve therapeutic efficacy in large animal models.

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Acknowledgements

We thank Dr David Resnick for his assistance with cloning of canine endostatin; Dr Arja Kaipainen for immunohistochemistry assistance; Drs Ilhan Celik and Oliver Kisker for their assistance with the BxPC-3 tumor model; Gustave Alberti for his assistance with mice; Susan Park for determining endostatin serum levels and helpful discussions; Kristen Gullage for photography. This work was supported by NIH Grants R01 CA064481, HL051818, HL066973 and the Breast Cancer Research Foundation.

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Author notes

  1. J Naspinski

    Present address: Merck Research Laboratories, Merck & Co., Inc., West Point, PA, USA

Authors and Affiliations

  1. Department of Surgery, Vascular Biology Program, Children's Hospital Boston, Harvard Medical School, Boston, MA, USA

    R M Tjin Tham Sjin, A E Birsner, R Chan, J Folkman & K Javaherian

  2. Gene Therapy Center and Department of Pharmacology, University of North Carolina, Chapel Hill, NC, USA

    J Naspinski, C Li & J Samulski

  3. EMD Lexington Research Center, Billerica, MA, USA

    K-M Lo & S Gillies

  4. Departments of Orthopaedic Surgery and Biostatistics, Children's Hospital Boston, Harvard Medical School, Boston, MA, USA

    D Zurakowski

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Correspondence to K Javaherian.

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Tjin Tham Sjin, R., Naspinski, J., Birsner, A. et al. Endostatin therapy reveals a U-shaped curve for antitumor activity. Cancer Gene Ther 13, 619–627 (2006). https://doi.org/10.1038/sj.cgt.7700938

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