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.
Highlights
One new viral gene delivery vector developed in attempt to overcome the hurdles of current viral vector systems is based on the insect baculovirus Autographa californica multiple nuclear polyhedrosis virus (AcMNPV)
The baculovirus has been thought to infect mainly insect cells until it has been shown that an expression of a reporter gene under the control of Rous sarcoma virus (RSV) promoter or cytomegalovirus immediate early (CMVIE) promoter was achieved in a human liver tumor cell line, HepG2 (Boyce and Bucher, 1996), and human hepatocytes (Hofmann et al, 1995), respectively
To investigate if the insect baculovirus can be used as a gene delivery vector to p53-defective tumors, several p53-deficient cell lines were screened for their susceptibility to a recombinant baculovirus containing a lacZ reporter gene (BV-lacZ)
Summary
One new viral gene delivery vector developed in attempt to overcome the hurdles of current viral vector systems is based on the insect baculovirus Autographa californica multiple nuclear polyhedrosis virus (AcMNPV). The baculovirus has been thought to infect mainly insect cells until it has been shown that an expression of a reporter gene (lacZ) under the control of Rous sarcoma virus (RSV) promoter or cytomegalovirus immediate early (CMVIE) promoter was achieved in a human liver tumor cell line, HepG2 (Boyce and Bucher, 1996), and human hepatocytes (Hofmann et al, 1995), respectively. One of the advantages of using this insect virus for delivering a therapeutic gene to mammalian cells is that, unlike any other animal viruses, it does not usually replicate in mammalian cells, a baculoviral vector can be much safer than current viral vectors. It is clear that AcMNPV can infect some mammalian cells and has useful features as a gene delivery vehicle, no one has shown the therapeutic use of a baculovirus yet
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