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- W1968654540 abstract "ell death receptors such as Fas/APO1/CD95 or the Tumor Necrosis Factor Receptor#1 (TNFR1) are potent inducers of apoptosis once overexpressed or engaged by their respective ligands Fas or Tumor Necrosis Factor (TNF) (see 1 and 2 for review).As systemic agents for cancer therapy, however, Fas and TNF have major limitations that have kept them out of the clinical armamentarium, namely side effects due to their lack of specificity for killing cancer cells. The TNF-related apoptosis-inducing ligand (TRAIL) is an exciting newcomer because it appears to specifically kill transformed and cancer cells but not normal cells (Fig. 1). Clues as to why TRAIL does not kill normal cells began to surface in 1997 when two TRAIL decoy receptors (TRID, Truncated Intracellular Domain, and TRUNDD, Truncated Death Domain) were cloned. These decoys were found to be expressed more on normal as compared to cancer cells and suggested to bind and compete away TRAIL from binding its two proapoptotic signaling receptors (DR4 and KILLER/DR5). Because of its promise, work has rapidly progressed to determine the feasibility and potential safety of bringing TRAIL into clinical trials. In the February 1999 issue of Nature Medicine, the group at Immunex Corporation led by David H.Lynch presents evidence for the safety and potential efficacy of TRAIL therapy against breast cancer in a Severe Combined Immunodeficiency (SCID) mouse model. They generated a recombinant molecule that has a modified leucine zipper (LZ) fused to either murine or human TRAIL (LZ-TRAIL).The leucine zipper permits trimerization of the soluble TRAIL cytokine which is believed to enhance its biological effects. In cell culture, the human LZ-TRAIL had no toxicity towards human mammary epithelial cells, human renal proximal tubule epithelial cells, normal human lung fibroblasts, or human skeletal muscle cells while demonstrating toxicity towards MDA-231 mammary adenocarcinoma cells at concentrations greater than 10 ng/ml LZ-TRAIL. Interestingly, LZ-TRAIL displayed a similar toxicity towards normal human astrocytes in culture. Intravenous injection of 200 μg of human LZ-TRAIL had no reported toxicity up to 24 h as assessed by observation and hematoxylin and eosin staining of liver and brain, whereas mice that received 50 μg of human LZ-CD95L (leucine zipper-Fas ligand fusion protein) were moribund within 55 min due to massive hepatocellular degeneration, necrosis and hemorrhage. Systemic administration of LZ-TRAIL twice daily for 10 days after intraperitoneal inoculation of CB17-SCID mice with 10 million MDA-231 breast cancer cells prolonged survival (all control mice were dead by 40–50 days whereas in C" @default.
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- W1968654540 date "1999-04-01" @default.
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- W1968654540 title "The TRAIL to an anti-cancer agent" @default.
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- W1968654540 doi "https://doi.org/10.1054/drup.1999.0075" @default.
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