title: Suppression of proliferative cholangitis by E2F decoy oligodeoxynucleotide.
abstract: BACKGROUND
  Proliferative cholangitis (PC) associated with hepatolithiasis results in stricture of the main bile ducts and is a major cause of residual and/or recurrent stones after repeated treatment for hepatolithiasis. The transcription factor E2F controls the expression of several genes involved in cell proliferation. The aim of this study was to inhibit PC using cytostatic gene therapy by transferring fusigenic anionic liposome-hemagglutinating virus of Japan (HVJ-anionic liposome) complexes containing a synthetic double-stranded oligodeoxynucleotide with high affinity for E2F (E2F decoy).
  
  
  METHODS
  PC was induced by introducing a fine nylon thread into the bile duct in a rat model. HVJ-anionic liposomes containing the E2F decoy were administered directly into the biliary tract. HVJ-anionic liposomes containing a missense oligodeoxynucleotide (scramble decoy) were also given as a control. The count of peribiliary glands in the bile duct, 5'-bromodeoxyuridine (BrdU) labeling index, and immunohistochemical staining for proliferating cell nuclear antigen (PCNA) in the bile duct were compared among untransfected, scramble decoy-transfected, and E2F decoy-transfected rats.
  
  
  RESULTS
  E2F decoy-transfected bile ducts showed inhibition of the papillary proliferation of the biliary epithelium and peribiliary gland hyperplasia. BrdU incorporation and PCNA expression in the bile ducts were inhibited in E2F decoy-transfected rats.
  
  
  CONCLUSIONS
  Our cytostatic gene therapy approach using direct E2F decoy transfer into the biliary tract suppressed PC in a rat model and may offer an effective therapeutic option for reducing recurrence following treatment for hepatolithiasis.
authors.affiliation: Department of Gastroenterological Surgery, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Yoshida
authors.forename: Naritaka
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Takashi
authors.initials: T
authors.lastname: Nitta
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Uehara
authors.forename: Ryuta
authors.initials: R
authors.lastname: Terao
authors.forename: Etsuro
authors.initials: E
authors.lastname: Hatano
authors.forename: Yuji
authors.initials: Y
authors.lastname: Iimuro
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Yamaoka
mesh_terms: D000818:Animals; D000963:Antimetabolites / Q000032:analysis / Q000493:pharmacokinetics; D001652:Bile Ducts / Q000473:pathology; D001973:Bromodeoxyuridine / Q000032:analysis / Q000493:pharmacokinetics; D018797:Cell Cycle Proteins; D002455:Cell Division / Q000235:genetics; D002761:Cholangitis / Q000473:pathology / Q000628:therapy*; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D015316:Genetic Therapy / Q000379:methods*; D007150:Immunohistochemistry; D008081:Liposomes; D008156:Luciferases / Q000235:genetics; D008297:Male; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D010957:Plasmids; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D029082:Sendai virus / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*; D014162:Transfection
chemical_list: D000963:Antimetabolites; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D008081:Liposomes; D009838:Oligodeoxyribonucleotides; D018809:Proliferating Cell Nuclear Antigen; D014157:Transcription Factors; D008156:Luciferases; D001973:Bromodeoxyuridine