Retroviral delivery and tetracycline-dependent expression of IL-1beta-converting enzyme (ICE) in a rat glioma model provides controlled induction of apoptotic death in tumor cells.
Interleukin 1beta-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 When tetracycline was withdrawn, ICE-lacZ gene expression was rapidly turned on and apoptosis-mediated cell death occurred in essentially all tumor cells.
Yu
J S
JS
Neurosurgery Service, Massachusetts General Hospital, Harvard Medical School, Charlestown 02129, USA.
Sena-Esteves
M
M
Paulus
W
W
Breakefield
X O
XO
Reeves
S A
SA
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001932:Brain Neoplasms / Q000473:pathology / Q000628:therapy*; D020170:Caspase 1; D003342:Corpus Striatum; D003546:Cysteine Endopeptidases / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D004790:Enzyme Induction / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D017930:Genes, Reporter; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics*; D018316:Gliosarcoma / Q000473:pathology / Q000628:therapy*; D008297:Male; D008979:Moloney murine leukemia virus / Q000235:genetics*; D009368:Neoplasm Transplantation; D011401:Promoter Regions, Genetic / Q000187:drug effects; D051381:Rats; D013752:Tetracycline / Q000494:pharmacology / Q000627:therapeutic use; D014162:Transfection
D003546:Cysteine Endopeptidases; D020170:Caspase 1; D013752:Tetracycline