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[Cancer Research 59, 2121-2126, May 1, 1999]
© 1999 American Association for Cancer Research
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[Cancer Research 59, 2121-2126, May 1, 1999]
© 1999 American Association for Cancer Research

Experimental Therapeutics

In Vivo Cytotoxicity of Ovarian Cancer Cells through Tumor-selective Expression of the BAX Gene1

Yu-Tzu Tai, Thomas Strobel, Donald Kufe and Stephen A. Cannistra2

Departments of Adult Oncology [Y-T. T., T. S., S. A. C.] and Cancer Pharmacology [D. K.], Dana-Farber Cancer Institute, and the Department of Hematology/Oncology, Beth Israel-Deaconess Medical Center [S. A. C.], Harvard Medical School, Boston, Massachusetts 02215

The BAX proapoptotic protein is capable of inducing 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. Two constructs were prepared using replication-deficient adenoviral vectors containing either the cDNA for ß-galactosidase (Ad.DF3.ßGAL) or hemagglutinin (HA)-tagged BAX (Ad.DF3.BAX) under the control of the DF3 promoter. The DF3 promoter was used to confer tumor-specific gene expression in view of its restricted pattern of expression in the majority of human ovarian cancers and its limited expression in normal peritoneal mesothelial cells. In vitro infection of up to seven different epithelial cancer cell lines with Ad.DF3.ßGAL or Ad.DF3.BAX resulted in expression of either ß-galactosidase activity or HA-BAX protein, respectively, which was highly correlated with DF3 levels. Furthermore, infection with Ad.DF3.BAX was capable of highly selective cytotoxicity of DF3-positive ovarian cancer clonogenic cells in vitro. The effect of i.p. administration of Ad.DF3.BAX was also assessed in nude mice inoculated with the DF3-positive 36M2 human ovarian cancer cell line. Expression of either ß- galactosidase activity (after Ad.DF3.ßGAL treatment) or HA-BAX transcripts (after Ad.DF3.BAX treatment) was restricted to tumor tissue in vivo. Importantly, administration of Ad.DF3.BAX on days 2 and 3 after tumor inoculation was capable of eradicating >99% of tumor implants. These results demonstrate the feasibility of tumor selective expression of a proapoptotic protein such as BAX through adenoviral gene transfer.




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Copyright © 1999 by the American Association for Cancer Research.