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Electrogene therapy using endostatin, with or without suicide gene therapy, suppresses murine mammary tumor growth and metastasis

Cancer Gene Therapy volume 14, pages 268–278 (2007)Cite this article

Abstract

Syngeneic inoculated metastatic mammary cancers received direct intratumoral injection of a plasmid vector containing either endostatin (pEndo) with or without a suicide gene (pHSVtk), pHSVtk alone or control vector once a week for 8 weeks. We applied electrogene transfer to the tumors after each injection and administered ganciclovir (GCV) to pHSVtk-transfected mice using an osmotic minipump. Anticancer efficacy was monitored using a variety of parameters, namely tumor volume, intratumoral microvessel density and DNA synthesis, number of mice with metastasis, and number of sites of metastasis per mouse. Tumor volume was significantly lower in all therapeutic groups, with the most effective growth suppression in the pEndo+pHSVtk/GCV group. Lymph node metastasis was significantly less frequent in all therapeutic groups, whereas the multiplicity of lung metastases was significantly lower only in the pEndo and pEndo+pHSVtk/GCV groups. All therapeutic groups showed significantly lower intratumor microvessel density and DNA synthesis. The pEndo and pEndo+pHSVtk/GCV groups also showed a significant reduction in the numbers of dilated lymphatic vessels containing intralumenal tumor cells. Our data suggest that endostatin electrogene therapy alone or in combination with pHSVtk/GCV suicide gene therapy is more beneficial than suicide gene therapy alone. The observed antimetastatic activity of endostatin may be of high clinical significance in the treatment of metastatic breast cancer.

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Abbreviations

HSVtk:

herpes simplex virus 1 thymidine kinase

HUVECs:

human umbilical vein endothelial cells

PI:

propidium iodide

TUNEL:

terminal deoxynucleotidyl transferase-mediated dUTP-digoxigenin nick end-labeling

vWF:

von Willebrand factor

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Acknowledgements

We thank Deborah E Devor-Henneman for critical review of the paper and Ms Hidemi Hiyama for warm-hearted secretarial assistance. This investigation was supported, in part, by the Development of Characteristic Education Grant from the Japan Private School Promotion Foundation (to MA Shibata), with main support from a Grant-in-Aid for Scientific Research (C)(2) from the Ministry of Education, Culture, Sports, Science and Technology of Japan (No. 15591368 to MA Shibata) and from a High-Tech Research Center Grant to Osaka Medical College from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

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Authors and Affiliations

  1. Department of Anatomy and Cell Biology, Division of Basic Medicine I, Osaka Medical College, 2-7, Daigaku-machi, Takatsuki, Osaka, Japan

    M-A Shibata, H Doi, S Morishima, M Naka & Y Otsuki

  2. High-Tech Research Center, Osaka Medical College, 2-7, Daigaku-machi, Takatsuki, Osaka, Japan

    M-A Shibata & Y Otsuki

  3. Laboratory Animal Center, Osaka Medical College, 2-7, Daigaku-machi, Takatsuki, Osaka, Japan

    J Morimoto

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  1. M-A Shibata
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Correspondence to M-A Shibata.

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Shibata, MA., Morimoto, J., Doi, H. et al. Electrogene therapy using endostatin, with or without suicide gene therapy, suppresses murine mammary tumor growth and metastasis. Cancer Gene Ther 14, 268–278 (2007). https://doi.org/10.1038/sj.cgt.7701009

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