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 Prepublished online as a Blood First Edition Paper on March 6, 2003; DOI 10.1182/blood-2002-07-2268.

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2002-07-2268v1
102/1/246    most recent
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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)


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