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Retroviral Delivery and Tetracycline-dependent Expression of IL-1ß-converting Enzyme (ICE) in a Rat Glioma Model Provides Controlled Induction of Apoptotic Death in Tumor Cells¹

Neurosurgery Service [J. S. Y., W. P., S. A. R.] and Neurology Service [J. S. Y., M. S-E., X. O. B.], Molecular Neurogenetics Unit [M. S-E., X. O. B.], and Molecular Neuro-Oncology [W. P., S. A. R.], Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129

Interleukin 1ß-converting enzyme (ICE) is a member of a growing family of cysteine proteases shown to be a crucial component in the activation of a genetic program that leads to autonomous cell death in mammalian cells. In this study, a murine ICE-lacZ fusion gene was introduced into a novel retroviral vector designed to achieve regulated ectopic expression of a foreign gene in mammalian cells. By delivering the ICE-lacZ gene within a retroviral vector and under the control of a tetracycline-regulated promoter, we were able to utilize the intrinsic cell death program of ICE as a means for tumoricidal therapy in a rat brain tumor model. Both in culture and in vivo suppression of ICE-lacZ expression was extremely tight in the presence of tetracycline, as determined by the lack of X-galactosidase-positive tumor cells and by cell viability. When tetracycline was withdrawn, ICE-lacZ gene expression was rapidly turned on and apoptosis-mediated cell death occurred in essentially all tumor cells.

¹ This work was supported in part by grants from the Charles E. Culpepper Foundation (J. S. Y.), National Institute of Neurological Disorders and Stroke Grant NS24279 (X. O. B.), and grants from the Preuss Brain Tumor Foundation (S. A. R.).

² To whom requests for reprints should be addressed, at Molecular Neuro-Oncology, Massachusetts General Hospital, Building 149, 13th Street, Charlestown, MA 02129. Phone: (617) 726-5510; Fax: (617) 726-5079; E-mail: reeves@helix.mgh.harvard.edu.

Received 6/10/96. Accepted 9/27/96.

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