title: Reduction of restenosis after angioplasty in an atheromatous rabbit model by suicide gene therapy.
abstract: BACKGROUND
  Gene delivery of the thymidine kinase (tk) gene combined with ganciclovir (GCV) limits intimal hyperplasia after abrasion of normal arteries. However, the low efficiency of adenoviral-mediated gene transfer to atherosclerotic arteries has raised concerns about the applicability of this strategy to the prevention of restenosis.
  
  
  RESULTS
  A replication-defective adenoviral vector expressing tk (Ad-RSVtk) demonstrated selective toxicity toward GCV-treated arterial smooth muscle cells, with oligonucleolytic cleavage suggesting apoptosis. In vivo, after demonstration of tk expression after Ad-RSVtk delivery, the combination of Ad-RSVtk followed by GCV was tested in a rabbit model of angioplasty of atheromatous iliac arteries. Angioplasty (8 atm, 20 minutes) was performed by use of a hydrogel balloon coated with Ad-RSVtk (4x10(9) plaque forming units). GCV was infused (25 mg.kg(-1) I.V. BID) from days 2 through 7 after angioplasty in 8 of 12 rabbits. Four weeks later, morphometric analysis demonstrated a reduced intima-to-media ratio in the group receiving combination therapy compared with Ad-RSVtk alone (3.0+/-1.2 versus 5.2+/-0.5, P<.018). GCV per se had no effect on intimal hyperplasia after arterial injury.
  
  
  CONCLUSIONS
  In vitro, Ad-RSVtk demonstrates selective toxicity toward GCV-treated arterial smooth muscle cells involving apoptosis. In vivo, GCV conditions reduction of neointimal formation after percutaneous delivery of Ad-RSVtk during angioplasty of atheromatous arteries.
authors.affiliation: INSERM U-460, Faculté Xavier Bichat, Paris, France.
authors.forename: P G
authors.initials: PG
authors.lastname: Steg
authors.forename: O
authors.initials: O
authors.lastname: Tahlil
authors.forename: N
authors.initials: N
authors.lastname: Aubailly
authors.forename: J M
authors.initials: JM
authors.lastname: Caillaud
authors.forename: J F
authors.initials: JF
authors.lastname: Dedieu
authors.forename: K
authors.initials: K
authors.lastname: Berthelot
authors.forename: A
authors.initials: A
authors.lastname: Le Roux
authors.forename: L
authors.initials: L
authors.lastname: Feldman
authors.forename: M
authors.initials: M
authors.lastname: Perricaudet
authors.forename: P
authors.initials: P
authors.lastname: Denèfle
authors.forename: D
authors.initials: D
authors.lastname: Branellec
mesh_terms: D000800:Angioplasty, Balloon; D000818:Animals; D001011:Aorta / Q000473:pathology*; D001161:Arteriosclerosis / Q000503:physiopathology / Q000628:therapy*; D016923:Cell Death / Q000235:genetics; D004195:Disease Models, Animal; D015774:Ganciclovir; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D011817:Rabbits; D012008:Recurrence; D013937:Thymidine Kinase / Q000235:genetics*; D017539:Tunica Intima / Q000473:pathology
chemical_list: D013937:Thymidine Kinase; D015774:Ganciclovir