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Prepublished online as a Blood First Edition Paper on July 25, 2002; DOI 10.1182/blood-2002-04-1096. This Article Full Text (PDF) All Versions of this Article: 2002-04-1096v1 100/12/3950    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Kikuchi, T. Articles by Nukiwa, T. Search for Related Content PubMed PubMed Citation Articles by Kikuchi, T. Articles by Nukiwa, T. Social Bookmarking                   What's this? Submitted April 10, 2002 Accepted July 8, 2002 Tumor Suppression Induced by Intratumor Administration of Adenovirus Vector Expressing NK4, a Four-Kringle Antagonist of Hepatocyte Growth Factor, and Naive Dendritic Cells Toshiaki Kikuchi*, Makoto Maemondo, Koh Narumi, Kunio Matsumoto, Toshikazu Nakamura, and Toshihiro Nukiwa Department of Respiratory Oncology and Molecular Medicine, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Miyagiken, Japan Division of Molecular Regenerative Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan * Corresponding author; email: kikuchi{at}idac.tohoku.ac.jp. NK4, a four-kringle antagonist of hepatocyte growth factor (HGF), is a potent inhibitor of tumor angiogenesis, and functions independently of its HGF-antagonistic activity. We have previously shown that in vivo genetic modification of tumors with an adenovirus vector that expresses NK4 (AdNK4) restrains tumor angiogenesis and slows the rate of tumor growth in vivo. In the present study, we investigated the hypothesis that this can be made more efficient by also administering bone marrow-generated dendritic cells (DCs) to the tumor. The data show that the growth of mouse subcutaneous tumors is significantly suppressed by direct administration of DCs into established tumors that had been pretreated with AdNK4 3 days previously. The synergistic antitumor effect produced by the combination therapy of AdNK4 with DCs correlated with the in vivo priming of tumor-specific cytotoxic T lymphocytes. Analysis of mice treated with fluorescence-labeled DCs suggested that DCs injected into the flank tumor could migrate to lymphoid organs in vivo for activation of immune-relevant processes. Knockout mice experiments demonstrated that the tumor regression produced by this combination therapy depends on both MHC class I antigen presentation of DCs injected into the tumors and CD8+ T cells of the treated host. Finally, a mechanism for this synergism was suggested by the histological observation that tumor necrosis and apoptosis were induced by genetic engineering of the tumors to express NK4. These findings should be useful in designing novel strategies that utilize a combination of two monotherapies directed against the vascular and immune systems for cancer therapy. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: W. Du, Y. Hattori, T. Yamada, K. Matsumoto, T. Nakamura, M. Sagawa, T. Otsuki, T. Niikura, T. Nukiwa, and Y. 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