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Published on: March 18, 2014
Combination treatment for osteosarcoma with baculoviral vector mediated gene therapy (p53) and chemotherapy
1Clinical Research Center, College of Medicine, Inha University, Inchon, Korea. sunuksong@inha.ac.kr
Abstract:
The insect baculovirus Autographa californica multiple nuclear polyhedrosis virus (AcMNPV) has been evaluated as a vector for gene delivery to human tumor cells. A human osteogenic sarcoma cell line, Saos-2, was found to be highly susceptible to infection with a baculoviral vector, with nearly 100% of Saos-2 cells being able to express a lacZ reporter gene after a brief exposure to the virus at a m.o.i. of 30 pfu/cell. The production of beta-galactosidase protein was 18-times greater than that in HepG2 cells which were previously thought to be the mammalian cells most susceptible to the baculovirus. The possibility of developing a baculovirus as a cytotoxic vector for p53-defective cancer was tested by destruction of Saos-2 cells (p53-/-) with a recombinant baculovirus containing the wild type p53 gene (BV-p53) in vitro. The p53 baculovirus induced apoptotic cell death in tumor cells in a dose-dependent manner with approximately 60% killing at an m.o.i. of 160 pfu/cell. Combined treatments of gene therapy (p53) and chemotherapy (adriamycin) resulted in synergistic and potent killing of the osteogenic sarcoma cells. For example, greater than 95% of Saos-2 cells were killed by the combination of BV-p53 (m.o.i. of 100) and adriamycin (35 ng/ml), whereas approximately 50% and approximately 55% cells were killed by BV-p53 and adriamycin alone, respectively. These results indicate that a baculoviral gene delivery vector can be used to efficiently target certain types of mammalian cells and the combination treatment of gene-therapy mediated by a baculovirus and chemotherapy may enhance induction of apoptosis in cancer cells.
Insights
Insect baculoviruses effectively deliver genes to human osteogenic sarcoma cells. Combining baculovirus-mediated p53 gene therapy with chemotherapy synergistically kills cancer cells, enhancing apoptosis for potential cancer treatment.
Area of Science:
- Molecular Biology
- Gene Therapy
- Virology
Background:
- Autographa californica multiple nuclear polyhedrosis virus (AcMNPV), an insect baculovirus, is explored as a gene delivery vector for human tumor cells.
- Previous studies suggested HepG2 cells were highly susceptible to baculovirus infection, but this study investigates a different cell line.
Purpose of the Study:
- To evaluate the efficacy of AcMNPV as a gene delivery vector in human osteogenic sarcoma (Saos-2) cells.
- To assess the potential of a recombinant baculovirus carrying the wild-type p53 gene (BV-p53) as a cytotoxic agent against p53-defective cancer cells.
- To investigate the synergistic effects of combining baculovirus-mediated p53 gene therapy with conventional chemotherapy (adriamycin).
Main Methods:
- Infection of Saos-2 cells with a lacZ reporter baculovirus to assess gene expression efficiency.
- Treatment of Saos-2 cells (p53-/-) with BV-p53 to evaluate induction of apoptotic cell death.
- Combined treatment of Saos-2 cells with BV-p53 and adriamycin to determine synergistic effects on cell killing.
Main Results:
- Saos-2 cells demonstrated high susceptibility to baculoviral infection, with nearly 100% expressing the lacZ reporter gene at a multiplicity of infection (m.o.i.) of 30 plaque-forming units (pfu)/cell.
- BV-p53 induced dose-dependent apoptotic cell death in Saos-2 cells, achieving approximately 60% killing at an m.o.i. of 160 pfu/cell.
- Combined BV-p53 (m.o.i. 100) and adriamycin (35 ng/ml) treatment resulted in synergistic cancer cell killing, with over 95% of Saos-2 cells killed, compared to approximately 50-55% killed by either treatment alone.
Conclusions:
- Baculoviral gene delivery vectors can efficiently target specific mammalian cell types, including osteogenic sarcoma cells.
- Baculovirus-mediated p53 gene therapy, particularly in combination with chemotherapy, shows significant potential for enhancing apoptosis and treating p53-defective cancers.
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