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Retroviral vector-mediated transfer of an antisense cyclin G1 construct inhibits osteosarcoma tumor growth in nude
1Department of Microbiology, Childrens Hospital of Los Angeles Research Institute, and the University of Southern California School of Medicine 90033, USA.
Abstract:
Metastatic osteosarcoma is a potential target for gene therapy, because conventional therapies are only palliative and metastatic disease is invariably fatal. Overexpression of the cyclin G1 (CYCG1) gene is frequently observed in human osteosarcoma cells, and its continued expression is found to be essential for their survival. Previously, we reported that down-regulation of cyclin G1 protein expression induced cytostatic and cytocidal effects in human MG-63 osteosarcoma cells (Skotzko et al., Cancer Research, 1995). Here, we extend these findings in a tumorigenic MNNG/HOS cell line and report on the effective inhibition of tumor growth in vivo by an antisense cyclin G1 retroviral vector when delivered as concentrated high titer vector supernatants directly into rapidly growing subcutaneous tumors in athymic nude mice. Histologic sections from the antisense cyclin G1 vector-treated tumors showed decreased mitotic indices and increased stroma formation within the residual tumors. Furthermore, in situ analysis of the cell-cycle kinetics of residual tumor cells revealed a decrease in the number of cells in S and G2/M phases of the cell cycle concomittant with an accumulation of cells in the G1 phase. Taken together, these studies demonstrate in vivo efficacy of a high-titer antisense cyclin G1 retroviral vector in an animal model of osteosarcoma.
Insights
Gene therapy targeting cyclin G1 (CYCG1) shows promise for metastatic osteosarcoma. An antisense CYCG1 retroviral vector effectively inhibited tumor growth in mice, offering a new therapeutic avenue.
Area of Science:
- Oncology
- Gene Therapy
- Molecular Biology
Background:
- Metastatic osteosarcoma is a fatal disease with limited treatment options.
- The cyclin G1 (CYCG1) gene is overexpressed in osteosarcoma and essential for cancer cell survival.
- Previous studies demonstrated that down-regulating CYCG1 induces cell death in osteosarcoma cells.
Purpose of the Study:
- To investigate the in vivo efficacy of an antisense CYCG1 retroviral vector in an osteosarcoma animal model.
- To evaluate the therapeutic potential of targeting CYCG1 for metastatic osteosarcoma.
Main Methods:
- Development and delivery of a high-titer antisense CYCG1 retroviral vector.
- Direct intratumoral injection of the vector into subcutaneous MNNG/HOS osteosarcoma xenografts in athymic nude mice.
- Histological analysis and in situ cell-cycle kinetic analysis of tumor tissues.
Main Results:
- The antisense CYCG1 retroviral vector significantly inhibited tumor growth in vivo.
- Histological examination revealed decreased mitotic indices and increased stroma formation in treated tumors.
- Cell-cycle analysis showed a decrease in S and G2/M phases with a concurrent accumulation in the G1 phase.
Conclusions:
- A high-titer antisense CYCG1 retroviral vector demonstrates in vivo efficacy against osteosarcoma.
- Targeting CYCG1 represents a promising gene therapy strategy for metastatic osteosarcoma.
- Further research into CYCG1-targeted gene therapy for osteosarcoma is warranted.