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Cancer Gene Therapy; Bax Gene Transfer Eradicates Ovarian
Cancer Cells
Cancer Weekly Plus via NewsEdge Corporation : (CW HENDERSON PUBLISHER www.newsfile.com) -- Adenovirus-mediated gene transfer of the bax gene in vivo eradicates human ovarian cancer inplants in mice.
Y.T. Tai and colleagues from Harvard University School of Medicine explored a gene therapy anticancer strategy based on the BAX proapoptotic protein (" In Vivo Cytotoxicity of Ovarian Cancer Cells Through Tumor-Selective Expression of the Bax Gene," Cancer Research, May 1, 1999;59(9):2121-2126).
Research has demonstrated that the BAX protein induces cell death either directly, through its effects on mitochondrial function, or indirectly, by lowering the apoptotic threshold in response to certain chemotherapy agents.
"In this study, we tested the hypothesis that selective expression of BAX in human ovarian cancer through adenoviral gene transfer might represent a novel approach to eradicating tumor cells in vivo," wrote Tai et al. "Two constructs were prepared using replication-deficient adenoviral vectors containing either the cDNA for beta-galactosidase (Ad.DF3.beta GAL) or hemagglutinin (HA)-tagged BAX (Ad.DF3.BAX) under the control of the DF3 promoter."
The researchers used the DF3 promoter to confer tumor-specific gene expression because it has a restricted pattern of expression in the majority of human ovarian cancers and has limited expression in normal peritoneal mesothelial cells.
In vitro experiments with infection of up to seven different epithelial cancer cell lines with Ad.DF3.beta GAL or Ad.DF3.BAX resulted in expression of either beta-galactosidase activity or HA-BAX protein, respectively, which was highly correlated with DF3 levels. In addition, in vitro infection with Ad.DF3.BAX was capable of highly selective cytotoxicity of DF3-positive ovarian cancer clonogenic cells.
They also assessed the effect of intraperitoneal (i.p.) administration of Ad.DF3.BAX in nude mice inoculated with the DF3-positive 36M2 human ovarian cancer cell line. Expression of either beta-galactosidase activity (after Ad.DF3.beta GAL treatment) or HA-BAX transcripts (after Ad.DF3.BAX treatment) was restricted to tumor tissue in vivo, noted the researchers.
Importantly, they observed that administration of Ad.DF3.BAX on days two and three after tumor inoculation was capable of eradicating >99 percent of tumor implants.
"These results demonstrate the feasibility of tumor selective expression of a proapoptotic protein such as BAX through adenoviral gene transfer," concluded Tai et al.
The corresponding author for this study is S.A. Cannistra, Harvard University, School of Medicine, Beth Israel Deaconess Medical Center, Department Hematology Oncology, E Campus, Kirstein 158, 330 Brookline Ave, Boston, Massachusetts 02215 USA.
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