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Potent bystander effect in suicide gene therapy using neural stem cells transduced with herpes simplex virus
Shaoyi Li1, Tsutomu Tokuyama, Junkoh Yamamoto
1Department of Neurosurgery, Hamamatsu University School of Medicine, Hamamatsu, Japan.
Objective:
The herpes simplex virus thymidine kinase (HSVtk)/ganciclovir suicide gene therapy system has been considered as one of the most promising therapeutic strategies for malignant gliomas. We have been using HSVtk gene-transduced neural stem cells (NSCtk) that possess an ability to migrate toward a tumor mass for the treatment of experimental brain tumors. In the present study, we evaluated the potency of anti-tumor effect mediated by the bystander effect between NSCtk and C6 glioma cells in the HSVtk/ganciclovir suicide gene therapy system.
Methods:
NSCtk and C6 glioma cells were mixed at various ratios (NSCtk:C6 cell ratios of 1:1 to 1:64) and the bystander effect was evaluated both under in vitro and in vivo conditions.
Results:
In vitro co-culture experiment showed a complete tumor growth inhibition at the NSCtk:C6 ratios as low as 1:16. In vivo co-implantation study in the rat brain showed no visible tumors at the NSCtk:C6 ratios as low as 1:16 and all those rats survived more than 100 days.
Conclusion:
The results clearly demonstrated an extremely potent bystander effect between NSCtk and C6 cells, and the minimum number of NSCtk cells needed for the treatment of tumors was roughly estimated.
Insights
Neural stem cells engineered with herpes simplex virus thymidine kinase (NSCtk) show potent anti-tumor effects against C6 glioma via bystander effects. This suicide gene therapy strategy effectively inhibits tumor growth and improves survival in experimental models.
Area of Science:
- Oncology
- Gene Therapy
- Neuroscience
Background:
- Malignant gliomas are challenging to treat.
- Herpes simplex virus thymidine kinase (HSVtk)/ganciclovir suicide gene therapy is a promising strategy.
- Neural stem cells (NSCtk) can migrate to tumor sites.
Purpose of the Study:
- To evaluate the anti-tumor efficacy of the HSVtk/ganciclovir suicide gene therapy system using NSCtk.
- To assess the bystander effect between NSCtk and C6 glioma cells.
Main Methods:
- Co-culturing NSCtk and C6 glioma cells at various ratios (1:1 to 1:64).
- Evaluating the bystander effect in vitro and in vivo (rat brain).
Main Results:
- Complete tumor growth inhibition observed in vitro at NSCtk:C6 ratios as low as 1:16.
- No visible tumors and >100 days survival in vivo at NSCtk:C6 ratios of 1:16.
Conclusions:
- A potent bystander effect exists between NSCtk and C6 glioma cells.
- The minimum effective dose of NSCtk for glioma treatment was estimated.
