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Treatment of Malignant Glioma Cells with the Transfer of Constitutively Active Caspase-6 Using the Human Telomerase Catalytic Subunit (Human Telomerase Reverse Transcriptase) Gene Promoter¹

Center for Surgery Research [T. Ko., Y. K., S. Kog., S. Kon.], Departments of Neurosurgery [T. Ko., S. Kon.] and Biomedical Engineering [S. H.], The Cleveland Clinic Foundation, Cleveland, Ohio 44195; Departments of Neurosurgery [T. Ko., Y. K., T. Ka., I. M. G., S. Kon.] and Biochemistry and Molecular Biology [H. S.], The Mount Sinai School of Medicine, New York, New York 10029; Center for Apoptosis Research and Department of Microbiology and Immunology, Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, Pennsylvania 19107 [S. M. S., E. S. A.]; RammelKamp Center for Education and Research, MetroHealth Medical Center, Cleveland, Ohio 44109 [B. P. B.]; Department of Obstetrics and Gynecology, Kanazawa University, School of Medicine, Kanazawa, Ishikawa 920-0934, Japan [M. T., M. I., S. Ky.]; and Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9039 [J. W. S.]

Because the apoptotic pathway is often disrupted in tumor cells, its genetic restoration is a very attractive approach for the treatment of tumors. To treat malignant gliomas with this approach, it would be preferred to restrict induction of apoptosis to tumor cells by establishing a tumor-specific expression system. Telomerase is an attractive target because the vast majority of malignant gliomas have telomerase activity whereas normal brain cells do not. Activation of telomerase is tightly regulated at the transcriptional level of the telomerase catalytic subunit [human telomerase reverse transcriptase, (hTERT)]. Therefore, we hypothesized that using a hTERT promoter-driven vector system, an apoptosis-inducible gene may be preferentially restricted to telomerase- or hTERT-positive tumor cells. In this study, we constructed an expression vector consisting of the constitutively active caspase-6 (rev-caspase-6) under the hTERT promoter (hTERT/rev-caspase-6) and then investigated its antitumor effect on malignant glioma cells. The rationale for using the rev-caspase-6 gene is because it induces apoptosis independent of the initiator caspases. We demonstrated that the hTERT/rev-caspase-6 construct induced apoptosis in hTERT-positive malignant glioma cells, but not in hTERT-negative astrocytes, fibroblasts, and alternative lengthening of telomeres cells. In addition, the growth of s.c. tumors in nude mice was significantly suppressed by the treatment with hTERT/rev-caspase-6 construct. The present results strongly suggest that the telomerase-specific transfer of the rev-caspase-6 gene under the hTERT promoter is a novel targeting approach for the treatment of malignant gliomas.

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