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Blood, 1 January 2007, Vol. 109, No. 1, pp. 306-314. Prepublished online as a Blood First Edition Paper on September 5, 2006; DOI 10.1182/blood-2006-03-013250. This Article Full Text (PDF) Supplemental Table and Figures All Versions of this Article: blood-2006-03-013250v1 109/1/306    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 CrossRef Citing Articles via Google Scholar Google Scholar Articles by Yokota, A. Articles by Maekawa, T. Search for Related Content PubMed PubMed Citation Articles by Yokota, A. Articles by Maekawa, T. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted March 28, 2006 Accepted August 15, 2006 INNO-406, a novel BCR-ABL/Lyn dual tyrosine kinase inhibitor, suppresses the growth of Ph+ leukemia cells in the central nervous system and cyclosporine A augments its in vivo activity Asumi Yokota, Shinya Kimura*, Satohiro Masuda, Eishi Ashihara, Junya Kuroda, Kiyoshi Sato, Yuri Kamitsuji, Eri Kawata, Yasuyuki Deguchi, Yoshimasa Urasaki, Yasuhito Terui, Martin Ruthardt, Takanori Ueda, Kiyohiko Hatake, Ken-ichi Inui, and Taira Maekawa Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital Department of Pharmacy, Kyoto University Hospital First Department of Internal Medicine, Fukui Medical University Division of Clinical Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Resear Department of Hematology, Johann Wolfgang Goethe-University * Corresponding author; email: shkimu{at}kuhp.kyoto-u.ac.jp. Central nervous system (CNS) relapse accompanying the prolonged administration of imatinib mesylate has recently become apparent as an impediment to the therapy of Philadelphia-chromosome-positive (Ph+) leukemia. CNS relapse may be explained by limited penetration of imatinib into the cerebrospinal fluid due to the presence of P-glycoprotein at the blood-brain barrier. To overcome imatinib-resistance mechanisms such as bcr-abl amplification, mutations within the ABL kinase domain, and activation of Lyn, we developed a dual BCR-ABL/Lyn inhibitor, INNO-406 (formerly NS-187), which is 25-55 times more potent than imatinib in vitro and at least 10 times more potent in vivo. The aim of this study was to investigate the efficacy of INNO-406 in treating CNS Ph+ leukemia. We found that INNO-406, like imatinib, is a substrate for P-glycoprotein. The concentrations of INNO-406 in the CNS were about 10% of those in the plasma. However, this residual concentration was enough to inhibit the growth of Ph+ leukemic cells which expressed not only wild type but also mutated BCR-ABL in the murine CNS. Furthermore, cyclosporine A, a P-glycoprotein inhibitor, augmented the in vivo activity of INNO-406 against CNS Ph+ leukemia. These findings indicate that INNO-406 is a promising agent for the treatment of CNS Ph+ leukemia. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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