Tumor vasculature-targeted delivery of tumor necrosis factor-α*

Authors

  • Anita Tandle PhD,

    1. Tumor Angiogenesis Section, Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
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  • Engy Hanna MS,

    1. Tumor Angiogenesis Section, Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
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  • Dominique Lorang PhD,

    1. Tumor Angiogenesis Section, Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
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  • Amin Hajitou PhD,

    1. Department of Gene Therapy, Division of Medicine, Imperial College London, Wright-Flemming Institute, St. Mary's Campus, London, United Kingdom
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  • Catherine A. Moya PhD,

    1. Department of Genitourinary Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
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  • Renata Pasqualini PhD,

    1. Department of Genitourinary Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
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  • Wadih Arap MD, PhD,

    1. Department of Genitourinary Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
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  • Asha Adem BA,

    1. Tumor Angiogenesis Section, Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
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  • Elizabeth Starker BA,

    1. Tumor Angiogenesis Section, Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
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  • Stephen Hewitt MD, PhD,

    1. Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
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  • Steven K. Libutti MD

    Corresponding author
    1. Tumor Angiogenesis Section, Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
    • Tumor Angiogenesis Section, Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 10, Room 4W-5940, 10 Center Drive, Bethesda, MD 20892===

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    • Fax: (301) 402-1788


  • We thank the National Institutes of Health Fellows Editorial Board for their editorial assistance in preparing the article.

  • *

    This article is a US government and, as such, is in the public domain in the United States of America.

Abstract

BACKGROUND: Recently, considerable efforts have been directed toward antivascular therapy as a new modality to treat human cancers. However, targeting a therapeutic gene of interest to the tumor vasculature with minimal toxicity to other tissues remains the objective of antivascular gene therapy. Tumor necrosis factor-α (TNF-α) is a potent antivascular agent but has limited clinical utility because of significant systemic toxicity. At the maximum tolerated doses of systemic TNF-α, there is no meaningful antitumor activity. Hence, the objective of this study was to deliver TNF-α targeted to tumor vasculature by systemic delivery to examine its antitumor activity. METHODS: A hybrid adeno-associated virus phage vector (AAVP) was used that targets tumor endothelium to express TNF-α (AAVP-TNF-α). The activity of AAVP-TNF-α was analyzed in various in vitro and in vivo settings using a human melanoma tumor model. RESULTS: In vitro, AAVP-TNF-α infection of human melanoma cells resulted in high levels of TNF-α expression. Systemic administration of targeted AAVP-TNF-α to melanoma xenografts in mice produced the specific delivery of virus to tumor vasculature. In contrast, the nontargeted vector did not target to tumor vasculature. Targeted AAVP delivery resulted in expression of TNF-α, induction of apoptosis in tumor vessels, and significant inhibition of tumor growth. No systemic toxicity to normal organs was observed. CONCLUSIONS: Targeted AAVP vectors can be used to deliver TNF-α specifically to tumor vasculature, potentially reducing its systemic toxicity. Because TNF-α is a promising antivascular agent that currently is limited by its toxicity, the current results suggest the potential for clinical translation of this strategy. Cancer 2009. Published 2008 by the American Cancer Society.

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