Mohamed Abdelaziz1, Lotfy Sherif2, Mostafa ElKhiary2, Sanjeeta Nair3, Shahinaz Shalaby4, Sara Mohamed2, Noura Eziba3, Mohamed El-Lakany3, David Curiel5, Nahed Ismail6, Michael P Diamond3, Ayman Al-Hendy7. 1. 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. 2. Department of Obstetrics and Gynecology, Mansoura Faculty of Medicine, Mansoura University Hospital, Mansoura, Egypt. 3. Department of Obstetrics and Gynecology, Georgia Regents University, Augusta, GA, USA. 4. Department of Pharmacology, Tanta Faculty of Medicine, Tanta, Egypt. 5. Department of Radiation Oncology, Washington University School of Medicine, St Louis, MO, USA. 6. Clinical Microbiology Division, University of Pittsburgh, Pittsburgh, PA, USA. 7. Department of Obstetrics and Gynecology, Georgia Regents University, Augusta, GA, USA aalhendy@gru.edu.
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. STUDY DESIGN: 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. MATERIALS AND 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. CONCLUSION: 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.
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 humanleiomyoma cells in vitro while sparing normal myometrial cells. STUDY DESIGN: 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. MATERIALS AND METHODS: Female nude mice were implanted with ratleiomyoma 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. CONCLUSION: 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: T P Cripe; E J Dunphy; A D Holub; A Saini; N H Vasi; Y Y Mahller; M H Collins; J D Snyder; V Krasnykh; D T Curiel; T J Wickham; J DeGregori; J M Bergelson; M A Currier Journal: Cancer Res Date: 2001-04-01 Impact factor: 12.701
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