title: Rationally designed hydrolytically activated etoposide prodrugs, a novel strategy for the treatment of neuroblastoma.
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.
authors.affiliation: Charité Children's Hospital, Experimental Oncology, Humboldt University, Augustenburger Platz 1, 13353 Berlin, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Lange
authors.forename: U
authors.initials: U
authors.lastname: Schroeder
authors.forename: N
authors.initials: N
authors.lastname: Huebener
authors.forename: J
authors.initials: J
authors.lastname: Jikai
authors.forename: J
authors.initials: J
authors.lastname: Wenkel
authors.forename: A
authors.initials: A
authors.lastname: Strandsby
authors.forename: W
authors.initials: W
authors.lastname: Wrasidlo
authors.forename: G
authors.initials: G
authors.lastname: Gaedicke
authors.forename: H N
authors.initials: HN
authors.lastname: Lode
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D001711:Biotransformation; D002470:Cell Survival / Q000187:drug effects; D017931:DNA Primers / Q000737:chemistry; D015195:Drug Design; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D005047:Etoposide / Q000494:pharmacology*; D005260:Female; D006801:Humans; D006868:Hydrolysis; D020714:Maximum Tolerated Dose; D051379:Mice; D009447:Neuroblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010957:Plasmids; D011355:Prodrugs / Q000138:chemical synthesis / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D017931:DNA Primers; D011355:Prodrugs; D005047:Etoposide