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Prepublished online as a Blood First Edition Paper on May 22, 2003; DOI 10.1182/blood-2003-01-0305. This Article Full Text (PDF) All Versions of this Article: 2003-01-0305v1 102/6/2229    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 Kuroda, J. Articles by Maekawa, T. Search for Related Content PubMed PubMed Citation Articles by Kuroda, J. Articles by Maekawa, T. Social Bookmarking                   What's this? Submitted January 31, 2003 Accepted May 13, 2003 The third-generation bisphosphonate Zoledronate synergistically augments the anti-Ph+ leukemia activity of imatinib mesylate Junya Kuroda, Shinya Kimura*, Hidekazu Segawa, Yutaka Kobayashi, Toshikazu Yoshikawa, Yoshimasa Urasaki, Takanori Ueda, Fumio Enjo, Harukuni Tokuda, Oliver G Ottmann, and Taira Maekawa Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, Kyoto, Japan First Department of Internal Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan Department of Gastroenterology and Hematology, Shiga University of Medical Science, Shiga, Japan First Department of Internal Medicine, Fukui Medical University, Fukui, Japan Department of Biochemistry, Kyoto Prefectural University of Medicine, Kyoto, Japan Department of Hematology, Johann Wolfgang Goethe University, Frankfurt, Germany * Corresponding author; email: shkimu{at}kuhp.kyoto-u.ac.jp. Imatinib mesylate, a competitive inhibitor of Abl tyrosine kinase, is highly effective for the early stages of chronic myelogeneous leukemia (CML), but remissions induced in advanced phase CML and Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia tend to be relatively short-lived. Therefore, the search for agents that enhance the anti-Ph+ effect of imatinib is warranted. We investigated the combined effects of imatinib and the third-generation bisphosphonate Zoledronate (ZOL) on Ph+ leukemias, because ZOL inhibited the prenylation of Ras-related proteins downstream of Bcr/Abl. First, we identified ZOL's potency in vitro against human leukemic cell lines, including two Ph+ and a P-glycoprotein overexpressing leukemic cell line. ZOL was also effective in vivo, as it prolonged the survival of NOD/SCID mice xenografted with Ph+ BV173 leukemic cells. Next, we showed the in vitro synergistic effects with ZOL and imatinib for Ph+ cell lines. ZOL combined with imatinib showed synergistic effects in vivo that prolonged the survival of mice inoculated with BV173. ZOL only minimally inhibited the growth of normal hematopoietic progenitors in vitro, and mice receiving ZOL and/or imatinib tolerated these treatments well. These findings indicate that ZOL is a potent anti-leukemic agent that augments synergistically the anti-Ph+ leukemia activity of imatinib. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: P. D. Ottewell, J. K. Woodward, D. V. Lefley, C. A. Evans, R. E. Coleman, and I. Holen Anticancer mechanisms of doxorubicin and zoledronic acid in breast cancer tumor growth in bone Mol. Cancer Ther., October 1, 2009; 8(10): 2821 - 2832. [Abstract] [Full Text] [PDF] E. Ashihara, E. Kawata, Y. Nakagawa, C. Shimazaski, J. Kuroda, K. Taniguchi, H. Uchiyama, R. Tanaka, A. Yokota, M. 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