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Rationally designed hydrolytically activated etoposide prodrugs, a novel strategy for the treatment of neuroblastoma
B Lange1, U Schroeder, N Huebener
1Charité Children's Hospital, Experimental Oncology, Humboldt University, Augustenburger Platz 1, 13353 Berlin, Germany.
Abstract:
Effective chemotherapy in neuroblastoma is limited by poor anti-tumor efficacy, systemic toxicity and the induction of drug resistance. Here, we provide further evidence that a hydrolytic activated prodrug design may overcome these problems. For this purpose, VP-16 was functionally blocked by a carbonate linker to generate two novel chemically stable prodrugs of VP-16, ProVP-16 I and II. We demonstrate profoundly different biological effects in vitro and in vivo of the prodrugs compared to parental VP-16. First, we established an up to >2 log higher in vitro toxicity of the two prodrugs compared to VP-16 on a panel of neuroblastoma cell lines. The highest increase of prodrug mediated cytotoxicity was observed in multi drug resistant cell lines. Second, in vivo studies showed a maximum tolerated dose (MTD) of ProVP-16 II (60 mg/kg), which was at least threefold higher than that of VP-16 (20 mg/kg). Tests of ProVP-16 II in a syngeneic NXS2 neuroblastoma model indicated that mice treated with this prodrug at 1/3 of the MTD was as effective as VP-16 parental compound used at the MTD in suppression of tumor growth. In summary, the etoposide prodrugs proved effective and less toxic and are therefore highly promising new anti-neuroblastoma compounds.
Insights
Novel etoposide (VP-16) prodrugs show enhanced anti-neuroblastoma efficacy and reduced toxicity. These compounds demonstrate superior in vitro cytotoxicity and improved in vivo safety profiles, offering promising new therapeutic options.
Area of Science:
- Oncology
- Pharmacology
- Drug Development
Background:
- Chemotherapy for neuroblastoma faces challenges including limited efficacy, systemic toxicity, and drug resistance.
- Etoposide (VP-16) is a key chemotherapeutic agent, but its clinical utility is constrained by these factors.
Purpose of the Study:
- To develop and evaluate novel hydrolytically activated prodrugs of etoposide (VP-16) designed to overcome the limitations of the parent drug.
- To assess the in vitro and in vivo anti-tumor efficacy and toxicity profiles of these novel VP-16 prodrugs in neuroblastoma models.
Main Methods:
- Synthesis of two novel VP-16 prodrugs, ProVP-16 I and II, utilizing a carbonate linker.
- In vitro evaluation of prodrug cytotoxicity against a panel of neuroblastoma cell lines, including multidrug-resistant variants.
- In vivo assessment of maximum tolerated dose (MTD) and anti-tumor efficacy in a syngeneic NXS2 neuroblastoma mouse model.
Main Results:
- ProVP-16 I and II exhibited significantly higher in vitro cytotoxicity (>2 log increase) compared to VP-16, particularly in multidrug-resistant neuroblastoma cell lines.
- ProVP-16 II demonstrated a substantially higher MTD (60 mg/kg) compared to VP-16 (20 mg/kg).
- In vivo, ProVP-16 II administered at one-third of its MTD showed comparable tumor growth suppression to VP-16 at its MTD in the NXS2 neuroblastoma model.
Conclusions:
- The novel etoposide prodrugs, ProVP-16 I and II, are effective against neuroblastoma.
- These prodrugs offer improved efficacy, reduced toxicity, and enhanced activity against drug-resistant neuroblastoma, representing promising new therapeutic candidates.
