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.
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Acknowledgements
The authors thank D. Williams, K. Mohler and M. Widmer for their critical comments and A. Aumell for her expert editorial help in the production of this manuscript. H. Walczak is supported by the AIDS Stipend Program of the Bundesministerium fur Forschung und Technologie (German Ministry for Research and Technology).
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Walczak, H., Miller, R., Ariail, K. et al. Tumoricidal activity of tumor necrosis factor–related apoptosis–inducing ligand in vivo. Nat Med 5, 157–163 (1999). https://doi.org/10.1038/5517
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DOI: https://doi.org/10.1038/5517
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