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Hydrolytically activated etoposide prodrugs inhibit MDR-1 function and eradicate established MDR-1
Ulrike Schroeder1, Kathrin M Bernt, Björn Lange
1Charité Children's Hospital, Humboldt university, Augustenburger Platz 1, 13353 Berlin, Germany.
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.
Insights
Novel etoposide (VP16) prodrugs demonstrate superior efficacy against drug-resistant leukemia. These prodrugs overcome multidrug resistance (MDR-1) mediated efflux, showing significant tumor regression in vivo.
Area of Science:
- Oncology
- Pharmacology
- Drug Development
Background:
- Established cytotoxic drugs for high-risk leukemia face limitations including poor efficacy, toxicity, and drug resistance.
- Multidrug resistance-1 (MDR-1) gene expression is a significant challenge in leukemia treatment.
- Novel therapeutic strategies are needed to overcome resistance to conventional chemotherapy.
Purpose of the Study:
- To develop and evaluate novel hydrolytically activated prodrugs of etoposide (VP16) to overcome drug resistance in leukemia.
- To assess the efficacy and safety of these VP16 prodrugs in vitro and in vivo models of drug-resistant leukemia.
Main Methods:
- Two novel VP16 prodrugs were synthesized using hydrolytically cleavable carbonate linkers.
- In vitro efficacy was tested on drug-resistant tumor cell lines and a VP16-resistant T-cell leukemia cell line (MOVP-3).
- In vivo studies evaluated maximum tolerated dose and therapeutic efficacy in a multidrug-resistant T-cell leukemia xenograft model.
Main Results:
- VP16 prodrugs exhibited over 3-log higher efficacy compared to VP16 against drug-resistant cell lines.
- Prodrugs successfully overcame MDR-1-mediated drug resistance by inhibiting MDR-1 efflux.
- ProVP16-II demonstrated a significantly higher maximum tolerated dose than VP16 in vivo.
- ProVP16-II achieved complete and durable regression of established, drug-resistant T-cell leukemia in a xenograft model.
Conclusions:
- Hydrolytically activated etoposide prodrugs are effective against multidrug-resistant T-cell leukemia in vitro and in vivo.
- These prodrugs offer a promising new strategy for treating MDR-1-mediated drug-resistant malignancies.
- The findings provide proof of concept for a novel approach to circumventing drug resistance in cancer therapy.