title: Effect of duplex drugs linking 2'-deoxy-5-fluorouridine (5-FdU) with 3'-C-ethynylcytidine (ECyd) on hepatoblastoma cell lines.
abstract: OBJECTIVE
  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 fibroblasts.
  
  
  METHODS
  The duplex drugs 2'-deoxy-5-fluorouridylyl-(3'-5')- 3'-C-ethynylcytidine (5-FdU(3'-5')ECyd) and 3'-C-ethynylcytidinylyl-(5'→1-O)-2-O-octadecyl-sn-glycerylyl-(3'-Ο→5')-2'-deoxy-5-fluorouridine (ECyd-lipid-5-FdU) were analysed in two HB cell lines (HUH6, HepT1) and fibroblasts by MTT assay. The treatment potential was compared to the single substances 2'-deoxy-5-fluorourindine (5-FdU), 3'-C-ethynylycytidine (ECyd) and an equimolar mixture of both. Cell cycle analyses were performed using flow cytometry after 7-AAD staining.
  
  
  RESULTS
  Both duplex drugs achieve a potent cytotoxic effect at low μM concentrations, which was more pronounced than the mixture of ECyd + 5-FdU. Further, both substances exert toxicity on fibroblasts of tumour samples, with less toxicity in foreskin fibroblasts cultures. Cell cycle analyses revealed a shift towards apoptotic cells for both drugs in HB cells.
  
  
  CONCLUSIONS
  5-FdU(3'-5')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.
authors.affiliation: Department of Pediatric Surgery and Pediatric Urology, University Children's Hospital Tuebingen, Hoppe-Seyler-Strasse 3, 72076, Tuebingen, Germany. carmen.eicher@med.uni-tuebingen.de
authors.forename: Carmen
authors.initials: C
authors.lastname: Eicher
authors.forename: Alexander
authors.initials: A
authors.lastname: Dewerth
authors.forename: Verena
authors.initials: V
authors.lastname: Ellerkamp
authors.forename: Joerg
authors.initials: J
authors.lastname: Fuchs
authors.forename: Sarah
authors.initials: S
authors.lastname: Schott
authors.forename: Sorin
authors.initials: S
authors.lastname: Armeanu-Ebinger
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003568:Cytidine Monophosphate / Q000008:administration & dosage / Q000031:analogs & derivatives*; D005434:Flow Cytometry / Q000379:methods; D005468:Fluorodeoxyuridylate / Q000008:administration & dosage / Q000031:analogs & derivatives*; D018197:Hepatoblastoma / Q000188:drug therapy*; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy*; D009841:Oligonucleotides / Q000008:administration & dosage*; D014407:Tumor Cells, Cultured
chemical_list: C576161:2'-deoxy-5-fluorouridylyl-(3'-5')-3'-C-ethynylcytidine; C576162:3'-C-ethynylcytidinylyl-(5'-1-O)-2-O-octadecyl-sn-glycerylyl-(3-O-5')-2'-deoxy-5-fluorouridine; D000964:Antimetabolites, Antineoplastic; D009841:Oligonucleotides; D005468:Fluorodeoxyuridylate; D003568:Cytidine Monophosphate