title: Hydrolytically activated etoposide prodrugs inhibit MDR-1 function and eradicate established MDR-1 multidrug-resistant T-cell leukemia.
abstract: 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.
authors.affiliation: Charité Children's Hospital, Humboldt university, Augustenburger Platz 1, 13353 Berlin, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Schroeder
authors.forename: Kathrin M
authors.initials: KM
authors.lastname: Bernt
authors.forename: Björn
authors.initials: B
authors.lastname: Lange
authors.forename: Jens
authors.initials: J
authors.lastname: Wenkel
authors.forename: Jiang
authors.initials: J
authors.lastname: Jikai
authors.forename: Doron
authors.initials: D
authors.lastname: Shabat
authors.forename: Roey
authors.initials: R
authors.lastname: Amir
authors.forename: Nicole
authors.initials: N
authors.lastname: Huebener
authors.forename: Andreas G
authors.initials: AG
authors.lastname: Niethammer
authors.forename: Christian
authors.initials: C
authors.lastname: Hagemeier
authors.forename: Lüder
authors.initials: L
authors.lastname: Wiebusch
authors.forename: Gerhard
authors.initials: G
authors.lastname: Gaedicke
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wrasidlo
authors.forename: Ralph A
authors.initials: RA
authors.lastname: Reisfeld
authors.forename: Holger N
authors.initials: HN
authors.lastname: Lode
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005047:Etoposide / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D006801:Humans; D006868:Hydrolysis; D020128:Inhibitory Concentration 50; D015458:Leukemia, T-Cell / Q000188:drug therapy / Q000473:pathology*; D051379:Mice; D008815:Mice, Inbred Strains; D011355:Prodrugs / Q000737:chemistry / Q000378:metabolism; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D011355:Prodrugs; D005047:Etoposide