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Hydrodynamics-based gene delivery of naked DNA encoding fetal liver kinase-1 gene effectively suppresses the growth of pre-existing tumors

Cancer Gene Therapy volume 13, pages 993–1001 (2006)Cite this article

Abstract

Antiangiogenic gene therapy is a promising strategy for cancer treatment, which generally requires highly efficient delivery systems. To date, success of this strategy has depended almost exclusively on the delivery of high titers of viral vectors, which can result in effective transgene expression. However, their cytotoxicity and immunogenicity are a major concern for clinical applications. Recent advances in delivery efficiency of naked DNA could potentially meet the requirement for both high transgene expression and minimal side effects. To investigate whether naked DNA can be used for antiangiogenic cancer therapy, an expression plasmid was generated that encodes a soluble form of fetal liver kinase-1 (Flk-1) gene, a receptor for vascular endothelial growth factor (VEGF). Hydrodynamic injection of this plasmid resulted in close to 0.1 mg/ml of soluble Flk-1 protein in mouse serum and blocked VEGF-driven angiogenesis in matrigel in vivo. The same delivery significantly suppressed the growth of two different pre-existing subcutaneous tumors, Renca renal cell carcinoma and 3LL lung carcinoma. CD31 immunohistochemistry revealed that the tumor-associated angiogenesis was also highly attenuated in soluble Flk-1-treated mice. Thus, expression of genes by hydrodynamics-based gene delivery of naked DNA appears to be a promising approach for antiangiogenic cancer gene therapy.

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Acknowledgements

We thank Dr John Ortaldo and Dr Jonathan Weiss for their critical review of this manuscript, the NCI, CCR Fellows Editorial Board for their editing, and Ms Susan Charbonneau and Ms Linda Grove for her excellent secretarial work. This work was partly supported by the Foreign Research Fellow Program funded by the Japanese Ministry of Education, Culture, Sports, Science and Technology. This project has been funded in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. N01-CO-12400.

The publisher or recipient acknowledges the right of the US Government to retain a non-exclusive, royalty-free license in and to any copyright covering the article.

Animal care was provided in accordance with the procedures outlined in the Guide for the Care and Use of Laboratory Animals (National Institutes of Health Publication no. 86–23, 1985).

The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government.

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  1. T Murakami

    Present address: RCAI, RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi-Ku, Yokohama City, Kanagawa, 230-0045, Japan

Authors and Affiliations

  1. Laboratory of Experimental Immunology, NCI Center for Cancer Research, Frederick, MD, USA

    H Yazawa, Y Suzuki, L Shorts, R H Wiltrout & M Watanabe

  2. Laboratory of Molecular Immunoregulation, NCI Center for Cancer Research, Frederick, MD, USA

    T Murakami & K Kurosaka

  3. Cell and Cancer Biology Branch, NCI Center for Cancer Research, Frederick, MD, USA

    H-M Li & E Parsoneault

  4. Basic Research Program, SAIC-Frederick Inc., NCI-Frederick, Frederick, MD, USA

    T Back

  5. Immunotherapy Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan

    Y Akiyama & K Maruyama

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Yazawa, H., Murakami, T., Li, HM. et al. Hydrodynamics-based gene delivery of naked DNA encoding fetal liver kinase-1 gene effectively suppresses the growth of pre-existing tumors. Cancer Gene Ther 13, 993–1001 (2006). https://doi.org/10.1038/sj.cgt.7700970

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