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Pediatr Surg Int (2013) 29:121127 DOI 10.1007/s00383-012-3192-5
ORIGINAL ARTICLE
Effect of duplex drugs linking 20-deoxy-5-uorouridine (5-FdU) with 30-C-ethynylcytidine (ECyd) on hepatoblastoma cell lines
Carmen Eicher Alexander Dewerth
Verena Ellerkamp Joerg Fuchs Sarah Schott
Sorin Armeanu-Ebinger
Published online: 28 November 2012 Springer-Verlag Berlin Heidelberg 2012
AbstractPurpose Duplex drugs are promising anticancer agents. After in vivo cleavage into active nucleoside analogues, they exert their anti-tumour activity with reduced toxicity and side effects. Here we evaluated the impact of two duplex drugs on the viability of hepatoblastoma (HB) cells lines and their toxicity against human broblasts. Methods The duplex drugs 20-deoxy-5-uorouridylyl-(30-50)- 30-C-ethynylcytidine (5-FdU(30-50)ECyd) and 30-C-ethynylcytidinylyl-(50?1-O)-2-O-octadecyl-sn-glycerylyl-(30-O ?50)-20-deoxy-5-uorouridine (ECyd-lipid-5-FdU) were analysed in two HB cell lines (HUH6, HepT1) and broblasts by
MTT assay. The treatment potential was compared to the single substances 20-deoxy-5-uorourindine (5-FdU), 30-C-ethynylycytidine (ECyd) and an equimolar mixture of both. Cell
cycle analyses were performed using ow cytometry after 7-AAD staining.
Results Both duplex drugs achieve a potent cytotoxic effect at low lM concentrations, which was more pronounced than the mixture of ECyd ? 5-FdU. Further, both substances exert toxicity on broblasts of tumour samples, with less toxicity in foreskin broblasts cultures. Cell cycle analyses revealed a shift towards apoptotic cells for both drugs in HB cells.
Conclusion 5-FdU(30-50)ECyd and ECyd-lipid-5-FdU exert a highly potent anti-tumoural effect on HB cells and might therefore be a treatment option in HB. Pharmacological formulations of both duplex drugs have to be evaluated in vivo to reduce possible side effects.
Keywords Hepatoblastoma Duplex drugs
20-deoxy-5-uorouridine 30-C-ethynylcytidine
Introduction
Hepatoblastoma (HB) is the most common solid liver tumour in childhood. However, it is rare and accounts for approximately 1 % of all paediatric malignancies [1]. Treatment results of children with HB strongly depend on the risk group, as in standard risk HB 3-year survival rates of 95 % can be achieved, while in patients with high risk or relapsed HB it remains poor with 67 % [2, 3]. The cyto-static regimen in HB is based on platin derivatives combined with further drugs depending on the preoperative staging (PRETEXT) [4]. Due to the different study groups, the chemotherapeutic regimens in high risk HB differ. The German Society for Paediatric Oncology (GPOH) uses carboplatin (CARBO) and etoposide (VP16), the International Society of Paediatric Oncology (SIOP) CARBO,