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Tumoricidal activity of tumor necrosis factor–related apoptosis–inducing ligand in vivo

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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Figure 1: Purified human and murine LZ–TRAIL are potent inducers of apoptosis in vitro.
Figure 2: Cross–species activity of LZ–huTRAIL and LZ–muTRAIL.
Figure 3: LZ–huTRAIL is cytotoxic to tumor cells but to not normal cells in vitro.
Figure 4: Acute effect of systemic administration of LZ–huTRAIL, LZ–muTRAIL and LZ–huCD95L.
Figure 5: Treatment of tumors in vivo with LZ–huTRAIL.
Figure 6: Effect of high–dose LZ–huTRAIL treatment on the growth of subcutaneously implanted tumors.
Figure 7: Histology of tumors from mice systemically treated with LZ–huTRAIL.

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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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Correspondence to David H. Lynch.

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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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