Abstract
An important safety concern on cell-based gene therapy is that few methods have been available to control the proliferation and functioning of therapeutic protein-expressing cells after transplantation. We previously reported that the proliferation and functioning of the cells transfected with herpes simplex virus thymidine kinase (HSVtk) gene, a suicide gene, can be controlled by administration of ganciclovir. In this study, we tried to control the amount of murine interferon-γ (IFN-γ) secreted from transplanted murine mesenchymal stem cell line C3H10T1/2 cells to achieve safe cell-based IFN-γ gene therapy for cancer. C3H10T1/2 cells were transfected with HSVtk- and murine IFN-γ-expressing plasmid vectors to obtain C3H10T1/2/HSVtk/IFN-γ cells. C3H10T1/2/HSVtk/IFN-γ cells released IFN-γ and were sensitive to ganciclovir. C3H10T1/2/HSVtk/IFN-γ cells significantly suppressed the proliferation of murine adenocarcinoma cell line colon26 cells both in vitro and in vivo. Moreover, subcutaneous administration of ganciclovir to mice transplanted with NanoLuc luciferase-expressing C3H10T1/2/HSVtk cells for three consecutive days reduced the luminescence signals from the transplanted cells. These results indicate that the cell regulation system using HSVtk gene and ganciclovir can be useful for safe and efficient cell-based IFN-γ gene therapy for cancer.
Highlights
An important safety concern on cell-based gene therapy is that few methods have been available to control the proliferation and functioning of therapeutic protein-expressing cells after transplantation
Cell suicide can cause the apoptosis of suicide gene-expressing cells in response to specific molecules, and we demonstrated that the proliferation and functioning of cells transfected with the herpes simplex thymidine kinase (HSVtk) gene, one of the suicide genes, could be regulated by administration of ganciclovir (GCV), a prodrug converted by herpes simplex virus thymidine kinase (HSVtk)
We examined whether the proliferation of transplanted C3H10T1/2/ HSVtk/IFN-γ cells could be regulated in mice by GCV administration, using C3H10T1/2/HSVtk cells expressing a reporter protein, NanoLuc luciferase (Nluc), for in vivo detection of the cells
Summary
An important safety concern on cell-based gene therapy is that few methods have been available to control the proliferation and functioning of therapeutic protein-expressing cells after transplantation. Subcutaneous administration of ganciclovir to mice transplanted with NanoLuc luciferase-expressing C3H10T1/2/ HSVtk cells for three consecutive days reduced the luminescence signals from the transplanted cells These results indicate that the cell regulation system using HSVtk gene and ganciclovir can be useful for safe and efficient cell-based IFN-γ gene therapy for cancer. Cell suicide can cause the apoptosis of suicide gene-expressing cells in response to specific molecules, and we demonstrated that the proliferation and functioning of cells transfected with the herpes simplex thymidine kinase (HSVtk) gene, one of the suicide genes, could be regulated by administration of ganciclovir (GCV), a prodrug converted by HSVtk. In this study, we tried to develop a safe cell-based interferon-γ (IFN-γ) gene therapy for cancer, by controlling the proliferation and functioning of the transplanted cells using the cell regulation system consisting of HSVtk gene and GCV. We examined whether the proliferation of transplanted C3H10T1/2/ HSVtk/IFN-γ cells could be regulated in mice by GCV administration, using C3H10T1/2/HSVtk cells expressing a reporter protein, NanoLuc luciferase (Nluc), for in vivo detection of the cells
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