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Adenovirus-mediated suicide-gene therapy in an orthotopic murine bladder tumor model
Jun Cheon1, Du Geon Moon, Hyun Yee Cho
1Department of Urology, Korea University College of Medicine, Seoul, Korea. jcheon@ns.kumc.or.kr
Background:
Patients with high-grade transitional-cell carcinoma (TCC) of the bladder frequently experience recurrence and progress and have a low response rate to chemotherapy in metastatic TCC. In this study, we evaluated the feasibility and long-term efficacy of suicide-gene therapy using adenovirus (Ad)-mediated herpes simplex virus thymidine kinase gene (HSV-TK) and prodrug ganciclovir (GCV) as a potential therapeutic approach in murine-orthotopic models of TCC.
Methods:
A replication defective adenoviral vectors containing toxic HSV-TK gene under the transcriptional control of RSV (Rous sarcoma virus) promoter (Ad-RSV-TK) was used. Orthotopic bladder TCC was established with 1 x 106 murine (MBT-2) TCC cells in syngenic C3H/He female mice. Intratumoral injection of Ad-RSV-TK in combination with GCV (20 mg/kg body weight/day i.p. b.i.d. x 7 days) was administered in vivo for the determination of treatment efficacy and long-term host survival in separate controlled experiments.
Results:
In vivo experiments demonstrated greater than three-fold reductions in MBT-2 tumor growth for the animals treated with Ad-RSV-TK (5 x 108 plaque forming units (pfu)/GCV therapy (P < 0.01)). Central tumor necrosis and apoptosis were revealed by histomorphology and immunohistochemistry compared with other control animals (non-treated, GCV alone, Ad-RSV-TK alone). Direct intratumoral injection with Ad-RSV-TK/GCV also resulted in significantly improved survival over the control groups in separated experiment (log-rank test, P < 0.05).
Conclusions:
Suicide-gene therapy using Ad-RSV-TK/GCV provides an effective therapy in an experimental murine orthotopic bladder cancer by significantly inhibiting tumor growth and improving long-term host survival.
Insights
Suicide-gene therapy using adenovirus-mediated herpes simplex virus thymidine kinase gene (Ad-RSV-TK) and ganciclovir (GCV) effectively inhibited bladder cancer growth in mice. This approach significantly improved long-term survival in experimental models.
Area of Science:
- Oncology
- Gene Therapy
- Cancer Research
Background:
- High-grade transitional-cell carcinoma (TCC) of the bladder often recurs and progresses.
- Metastatic TCC shows limited response to conventional chemotherapy.
- Novel therapeutic strategies are needed for advanced bladder cancer.
Purpose of the Study:
- To evaluate the feasibility of suicide-gene therapy for bladder cancer.
- To assess the long-term efficacy of adenovirus-mediated herpes simplex virus thymidine kinase gene (HSV-TK) and ganciclovir (GCV) therapy.
- To investigate this approach in a murine-orthotopic TCC model.
Main Methods:
- Utilized a replication-defective adenoviral vector (Ad-RSV-TK) containing the HSV-TK gene.
- Established orthotopic bladder TCC in syngenic C3H/He female mice using MBT-2 cells.
- Administered intratumoral Ad-RSV-TK combined with systemic ganciclovir (GCV) in vivo.
Main Results:
- Ad-RSV-TK/GCV therapy resulted in over a three-fold reduction in tumor growth (P < 0.01).
- Histomorphology and immunohistochemistry confirmed central tumor necrosis and apoptosis.
- Significantly improved long-term host survival compared to control groups (P < 0.05).
Conclusions:
- Suicide-gene therapy with Ad-RSV-TK/GCV is an effective treatment for experimental murine orthotopic bladder cancer.
- This therapy significantly inhibits tumor growth.
- It also improves long-term host survival in preclinical models.