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Prepublished online as a Blood First Edition Paper on March 6, 2003; DOI 10.1182/blood-2002-07-2268.
Submitted August 5, 2002
Accepted February 8, 2003
Hydrolytically activated etoposide prodrugs inhibit MDR-1 function and eradicate established MDR-1 multidrug resistant T-cell leukemia
Ulrike Schroeder, Kathrin M Bernt, Bjoern Lange, Jens Wenkel, Jiang Jikai, Doron Shabat, Roey Amir, Nicole Huebener, Andreas G Niethammer, Christian Hagemeier, Lueder Wiebusch, Gerhard Gaedicke, Wolfgang Wrasidlo, Ralph A Reisfeld, and Holger N Lode*
Department of Pediatrics, Charite Children's Hospital, Berlin, Germany
Tel-Aviv University School of Chemistry, Tel-Aviv, Israel
Department of Immunology, The Scripps Research Institute, La Jolla, CA, USA
* Corresponding author; email: holger.lode{at}charite.de.
Effective therapy of high-risk leukemia with established cytotoxic drugs may be limited by poor anti-tumor efficacy, systemic toxicity and the induction of drug resistance. Here, we provide the first evidence that hydrolytic activated prodrugs may overcome these problems. For this purpose, VP-16 was functionally blocked by hydrolytically cleavable carbonate linkers with unique characteristics to generate two novel prodrugs of VP-16. First, we established a > 3 log higher efficacy of the two prodrugs compared to VP16 on a panel of naturally drug resistant tumor cell lines. Second, the prodrugs did overcome artificially VP-16-induced multidrug resistance in vitro in a newly established VP-16 resistant T-cell leukemia cell line MOVP-3 by functionally blocking MDR-1 mediated efflux. Third, in vivo studies showed a maximum tolerated dose (MTD) of ProVP-16 II (>45mg/kg), which was at least 3-fold higher than that of VP-16 (15 mg/kg). Finally, tests of ProVP-16 II in a multidrug resistant xenograft model of T-cell leukemia expressing MDR-1 indicated that only 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.
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