Abstract
To evaluate the utility of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) as a cancer therapeutic, we created leucine zipper (LZ) forms of human (hu) and murine (mu) TRAIL to promote and stabilize the formation of trimers. Both were biologically active, inducing apoptosis of both human and murine target cells in vitro with similar specific activities. In contrast to the fulminant hepatotoxicity of LZ-huCD95L in vivo, administration of either LZ-huTRAIL or LZ-muTRAIL did not seem toxic to normal tissues of mice. Finally, repeated treatments with LZ-huTRAIL actively suppressed growth of the TRAIL-sensitive human mammary adenocarcinoma cell line MDA-231 in CB.17 (SCID) mice, and histologic examination of tumors from SCID mice treated with LZ-huTRAIL demonstrated clear areas of apoptotic necrosis within 9-12 hours of injection.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / pharmacology*
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Apoptosis / drug effects*
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Apoptosis Regulatory Proteins
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Dose-Response Relationship, Drug
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Fas Ligand Protein
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Humans
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Membrane Glycoproteins / administration & dosage
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Membrane Glycoproteins / chemical synthesis
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Membrane Glycoproteins / pharmacology*
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Mice, SCID
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Protein Conformation
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TNF-Related Apoptosis-Inducing Ligand
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Tumor Cells, Cultured
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Tumor Necrosis Factor-alpha / administration & dosage
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Tumor Necrosis Factor-alpha / chemical synthesis
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Tumor Necrosis Factor-alpha / pharmacology*
Substances
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Antineoplastic Agents
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Apoptosis Regulatory Proteins
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FASLG protein, human
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Fas Ligand Protein
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Fasl protein, mouse
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Membrane Glycoproteins
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TNF-Related Apoptosis-Inducing Ligand
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TNFSF10 protein, human
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Tnfsf10 protein, mouse
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Tumor Necrosis Factor-alpha