title: Targeted Adenoviral Vector Demonstrates Enhanced Efficacy for In Vivo Gene Therapy of Uterine Leiomyoma.
abstract: BACKGROUND
  Gene therapy is a potentially effective non-surgical approach for the treatment of uterine leiomyoma. We demonstrated that targeted adenovirus vector, Ad-SSTR-RGD-TK/GCV, was highly effective in selectively inducing apoptosis and inhibiting proliferation of human leiomyoma cells in vitro while sparing normal myometrial cells.
  
  
  METHODS
  An in-vivo study, to compare efficacy and safety of modified adenovirus vector Ad-SSTR-RGD-TK/GCV versus untargeted vector for treatment of leiomyoma.
  
  
  METHODS
  Female nude mice were implanted with rat leiomyoma cells subcutaneously. Then mice were randomized into three groups. Group 1 received Ad-LacZ (marker gene), Group 2 received untargeted Ad-TK, and Group 3 received the targeted Ad-SSTR-RGD-TK. Tumors were measured weekly for 4 weeks. Then mice were sacrificed and tissue samples were collected. Evaluation of markers of apoptosis, proliferation, extracellular matrix, and angiogenesis was performed using Western Blot & Immunohistochemistry. Statistical analysis was done using ANOVA. Dissemination of adenovirus was assessed by PCR.
  
  
  RESULTS
  In comparison with the untargeted vector, the targeted adenoviral vector significantly shrank leiomyoma size (P < 0.05), reduced expression of proliferation marker (PCNA) (P < 0.05), induced expression of apoptotic protein, c-PARP-1, (P < 0.05) and inhibited expression of extracellular matrix-related genes (TGF beta 3) and angiogenesis-related genes (VEGF & IGF-1) (P < 0.01). There were no detectable adenovirus in tested tissues other than leiomyoma lesions with both targeted and untargeted adenovirus.
  
  
  CONCLUSIONS
  Targeted adenovirus, effectively reduces tumor size in leiomyoma without dissemination to other organs. Further evaluation of this localized targeted strategy for gene therapy is needed in appropriate preclinical humanoid animal models in preparation for a future pilot human trial.
authors.affiliation: Department of Obstetrics and Gynecology, Mansoura Faculty of Medicine, Mansoura University Hospital, Mansoura, Egypt Department of Obstetrics and Gynecology, Georgia Regents University, Augusta, GA, USA.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Abdelaziz
authors.affiliation: Department of Obstetrics and Gynecology, Mansoura Faculty of Medicine, Mansoura University Hospital, Mansoura, Egypt.
authors.forename: Lotfy
authors.initials: L
authors.lastname: Sherif
authors.affiliation: Department of Obstetrics and Gynecology, Mansoura Faculty of Medicine, Mansoura University Hospital, Mansoura, Egypt.
authors.forename: Mostafa
authors.initials: M
authors.lastname: ElKhiary
authors.affiliation: Department of Obstetrics and Gynecology, Georgia Regents University, Augusta, GA, USA.
authors.forename: Sanjeeta
authors.initials: S
authors.lastname: Nair
authors.affiliation: Department of Pharmacology, Tanta Faculty of Medicine, Tanta, Egypt.
authors.forename: Shahinaz
authors.initials: S
authors.lastname: Shalaby
authors.affiliation: Department of Obstetrics and Gynecology, Mansoura Faculty of Medicine, Mansoura University Hospital, Mansoura, Egypt.
authors.forename: Sara
authors.initials: S
authors.lastname: Mohamed
authors.affiliation: Department of Obstetrics and Gynecology, Georgia Regents University, Augusta, GA, USA.
authors.forename: Noura
authors.initials: N
authors.lastname: Eziba
authors.affiliation: Department of Obstetrics and Gynecology, Georgia Regents University, Augusta, GA, USA.
authors.forename: Mohamed
authors.initials: M
authors.lastname: El-Lakany
authors.affiliation: Department of Radiation Oncology, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: David
authors.initials: D
authors.lastname: Curiel
authors.affiliation: Clinical Microbiology Division, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Nahed
authors.initials: N
authors.lastname: Ismail
authors.affiliation: Department of Obstetrics and Gynecology, Georgia Regents University, Augusta, GA, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Diamond
authors.affiliation: Department of Obstetrics and Gynecology, Georgia Regents University, Augusta, GA, USA aalhendy@gru.edu.
authors.forename: Ayman
authors.initials: A
authors.lastname: Al-Hendy
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D018390:Gene Targeting / Q000379:methods*; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000235:genetics; D006801:Humans; D007889:Leiomyoma / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008819:Mice, Nude; D011897:Random Allocation; D051381:Rats; D014594:Uterine Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*
keywords: adenovirus vectors; gene therapy; thymidine kinase/apoptosis; uterine leiomyoma