Rationally designed hydrolytically activated etoposide prodrugs, a novel strategy for the treatment of neuroblastoma.
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.
Lange
B
B
Charité Children's Hospital, Experimental Oncology, Humboldt University, Augustenburger Platz 1, 13353 Berlin, Germany.
Schroeder
U
U
Huebener
N
N
Jikai
J
J
Wenkel
J
J
Strandsby
A
A
Wrasidlo
W
W
Gaedicke
G
G
Lode
H N
HN
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
D000972:Antineoplastic Agents, Phytogenic; D017931:DNA Primers; D011355:Prodrugs; D005047:Etoposide