SEARCH:   Advanced

Prepublished online as a Blood First Edition Paper on March 6, 2003; DOI 10.1182/blood-2002-07-2268. This Article Full Text Full Text (PDF) All Versions of this Article: 2002-07-2268v1 102/1/246    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map 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 Schroeder, U. Articles by Lode, H. N. Search for Related Content PubMed PubMed Citation Articles by Schroeder, U. Articles by Lode, H. N. Related Collections Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Hydrolytically activated etoposide prodrugs inhibit MDR-1 function and eradicate established MDR-1 multidrug-resistant T-cell leukemia Ulrike Schroeder, Kathrin M. Bernt, Björn Lange, Jens Wenkel, Jiang Jikai, Doron Shabat, Roey Amir, Nicole Huebener, Andreas G. Niethammer, Christian Hagemeier, Lüder Wiebusch, Gerhard Gaedicke, Wolfgang Wrasidlo, Ralph A. Reisfeld, and Holger N. Lode From the Charité Children's Hospital, Humboldt University, Berlin, Germany; School of Chemistry, Tel Aviv University, Tel Aviv, Israel; the Scripps Research Institute, Department of Immunology, La Jolla, CA. Effective therapy of high-risk leukemia with established cytotoxic drugs may be limited by poor antitumor efficacy, systemic toxicity, and the induction of drug resistance. Here, we provide the first evidence that hydrolytically activated prodrugs may overcome these problems. For this purpose, VP16 was functionally blocked by hydrolytically cleavable carbonate linkers with unique characteristics to generate 2 novel prodrugs of VP16. First, we established a more than 3-log higher efficacy of the 2 prodrugs compared with VP16 on a panel of naturally drug-resistant tumor cell lines. Second, the prodrugs did overcome VP16-induced multidrug resistance-1 gene (MDR-1)—mediated multidrug resistance in vitro in a newly established VP16-resistant T-cell leukemia cell line MOVP-3 by functionally blocking MDR-1—mediated efflux. Third, in vivo studies showed a maximum tolerated dose of ProVP16-II (> 45mg/kg), which was at least 3-fold higher than that of VP16 (15 mg/kg). Finally, tests of ProVP16-II in a multidrug-resistant xenograft model of T-cell leukemia expressing MDR-1 indicated that only the mice treated with this prodrug revealed a complete and long-lasting regression of established, drug-resistant leukemia. In summary, the hydrolytically activated etoposide prodrugs proved effective against multidrug-resistant T-cell leukemia in vitro and in vivo and provide proof of concept for a highly promising new strategy for the treatment of MDR-1 drug-resistant malignancies. (Blood. 2003;102:246-253) CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: W. Hiddemann, M. Kneba, M. Dreyling, N. Schmitz, E. Lengfelder, R. Schmits, M. Reiser, B. Metzner, H. Harder, S. Hegewisch-Becker, et al. Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome for patients with advanced-stage follicular lymphoma compared with therapy with CHOP alone: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group Blood, December 1, 2005; 106(12): 3725 - 3732. [Abstract] [Full Text] [PDF] G. Lenz, M. Dreyling, E. Schiegnitz, T. Haferlach, J. Hasford, M. Unterhalt, and W. Hiddemann Moderate Increase of Secondary Hematologic Malignancies After Myeloablative Radiochemotherapy and Autologous Stem-Cell Transplantation in Patients With Indolent Lymphoma: Results of a Prospective Randomized Trial of the German Low Grade Lymphoma Study Group J. Clin. Oncol., December 15, 2004; 22(24): 4926 - 4933. [Abstract] [Full Text] [PDF] G. Lenz, M. Dreyling, E. Schiegnitz, R. Forstpointner, H. Wandt, M. Freund, G. Hess, L. Truemper, V. Diehl, M. Kropff, et al. Myeloablative radiochemotherapy followed by autologous stem cell transplantation in first remission prolongs progression-free survival in follicular lymphoma: results of a prospective, randomized trial of the German Low-Grade Lymphoma Study Group Blood, November 1, 2004; 104(9): 2667 - 2674. [Abstract] [Full Text] [PDF]

	Copyright © 2003 by American Society of Hematology         Online ISSN: 1528-0020