Safety and antitumor activity of recombinant soluble Apo2 ligand

Ashkenazi, Avi; Pai, Roger; Fong, Sharon; Leung, Susan W.S.; Lawrence, David A.; Marsters, Scot A.; Blackie, Christine; Chang, Ling; McMurtrey, Amy E.; Hebert, Andrea; DeForge, Laura; Koumenis, Iphigenia L.; Lewis, D. K.; Harris, Louise A.; Bussiere, Jeanine L.; Koeppen, Hartmut; Shahrokh, Zahra; Schwall, Ralph

doi:10.1172/jci6926

Cited by 2,027 publications

(1,844 citation statements)

References 37 publications

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“…In this regard, the effects of TRAIL-induced injury in primary endothelial cells are not unique. The observation of Li et al (2003) that primary endothelial cells are susceptible to TRAIL death signals differ from those reported previously by others (Ashkenazi et al, 1999;Walczak et al, 1999). However, although Li et al (2003) found that TRAIL, compared to TNF, is potent at causing injury, it was less effective at stimulating inflammation in endothelial cells.…”

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confidence: 59%

“…TRAIL is suggested to induce apoptosis preferentially in a wide range of transformed cell lines, while most normal cells were resistant both in vitro (Wiley et al, 1995;Pitti et al, 1996) and in vivo (Walczak et al, 1997;Ashkenazi et al, 1999). In contrast, injection of other death ligands such as CD95-L or TNF-a results in massive degeneration of normal tissue (Ashkenazi et al, 1999).…”

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confidence: 99%

“…In contrast, injection of other death ligands such as CD95-L or TNF-a results in massive degeneration of normal tissue (Ashkenazi et al, 1999). The tumour selectivity and safety of soluble recombinant TRAIL in vivo have been examined in various studies, and it was generally found to be well tolerated even when multiple doses were administered to animals (Ashkenazi et al, 1999;Walczak et al, 1999;Fulda et al, 2002).…”

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Induction of apoptosis in experimental human B cell lymphomas by conditional TRAIL-expressing T cells

et al. 2003

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In the present study, we demonstrate the utility of a non-tumour-forming T-cell line for the inducible gene transfer of tumour necrosis factor (TNF)-related apoptosis-inducing ligand (Apo2L/TRAIL), which has been shown to selectively induce apoptosis in malignant but not in normal cells. To generate T cells inducible for TRAIL expression, we stably transfected Jurkat cells with TRAIL in the context of the Tet-On system. The switched on cells strongly expressed TRAIL mRNA, whose protein product was expressed on the cell surface. Paracrine induction of apoptosis in human target tumour cells was solely found for membrane-bound TRAIL. The Jurkat-TRAIL cells itself survived due to clonal selection of TRAIL-resistant cells. Jurkat-TRAIL cells had an additive effect with cytotoxic drugs in vitro, since cell death was enhanced. To elucidate the antitumoral activity of these Jurkat-TRAIL cells in vivo, we injected them intratumorally in xenografts of human Burkitt lymphomas. Switching on expression of TRAIL by adding tetracycline to the drinking water of the mice strongly reduced tumour growth by apoptosis in a caspase-dependent manner. Thus, non-tumourforming T-cell lines offer a novel method for gene transfer and inducible expression of TRAIL in tumour therapy.

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Induction of apoptosis in experimental human B cell lymphomas by conditional TRAIL-expressing T cells

et al. 2003

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“…Tumor necrosis factor-related apoptosis-inducing ligand induces apoptosis in most tumour cells, while many normal tissues and cells, respectively, are relatively resistant to apoptosis (Ashkenazi et al, 1999;Walczak et al, 1999;Belka et al, 2004). This finding created great interest and suggested TRAIL or anti-DR5 antibodies, respectively, as potential anticancer drugs (Fulda and Debatin, 2004).…”

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confidence: 99%

TRAIL activates acid sphingomyelinase via a redox mechanism and releases ceramide to trigger apoptosis

2006

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We have previously shown that activation of the acid sphingomyelinase (ASM), the release of ceramide and the formation of ceramide-enriched membrane domains are central for the induction of apoptosis by CD95. Here, we demonstrate that tumor necrosis factor-related apoptosisinducing ligand (TRAIL) and CD95 activate the ASM via a redox mechanism resulting in release of ceramide and formation of ceramide-enriched membrane platforms. Ceramide-enriched membrane platforms serve to cluster DR5 upon stimulation. Antioxidants prevent TRAILmediated stimulation of ASM, the release of ceramide, the formation of ceramide-enriched membrane platforms and the induction of apoptosis by TRAIL. Further, ASMdeficient splenocytes fail to cluster DR5 in ceramideenriched membrane domains upon TRAIL stimulation and resist TRAIL-induced apoptosis, events that were restored by addition of natural C 16 -ceramide. A dose-response analysis indicates that ceramide-enriched membrane platforms greatly sensitized tumor cells to TRAIL-induced apoptosis. Our data indicate that ceramide-enriched membrane platforms are required for the signaling of TRAIL-DR5 complexes under physiological conditions.

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“…It induces apoptosis in many cancer cell lines, with minimal to no effect on most normal cells (Wiley et al, 1995;Pitti et al, 1996;KothnyWilkes et al, 1998;Ashkenazi et al, 1999;Walczak et al, 1999;Lawrence et al, 2001;Evdokiou et al, 2002). TRAIL mediates apoptosis through two death receptors, TRAIL-receptor 1 (TRAIL-R1, DR4, TNFRSF10A) and TRAIL-receptor 2 (TRAIL-R2, DR5, TNFRSF10B).…”

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HGS-ETR1, a fully human TRAIL-receptor 1 monoclonal antibody, induces cell death in multiple tumour types in vitro and in vivo

et al. 2005

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Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in a variety of tumour cells through activation of TRAIL-R1 and TRAIL-R2 death signalling receptors. Here, we describe the characterisation and activity of HGS-ETR1, the first fully human, agonistic TRAIL-R1 mAb that is being developed as an antitumour therapeutic agent. HGS-ETR1 showed specific binding to TRAIL-R1 receptor. HGS-ETR1 reduced the viability of multiple types of tumour cells in vitro, and induced activation of caspase 8, Bid, caspase 9, caspase 3, and cleavage of PARP, indicating activation of TRAIL-R1 alone was sufficient to induce both extrinsic and intrinsic apoptotic pathways. Treatment of cell lines in vitro with HGS-ETR1 enhanced the cytotoxicity of chemotherapeutic agents (camptothecin, cisplatin, carboplatin, or 5-fluorouracil) even in tumour cell lines that were not sensitive to HGS-ETR1 alone. In vivo administration of HGS-ETR1 resulted in rapid tumour regression or repression of tumour growth in pre-established colon, non-smallcell lung, and renal tumours in xenograft models. Combination of HGS-ETR1 with chemotherapeutic agents (topotecan, 5-fluorouracil, and irinotecan) in three independent colon cancer xenograft models resulted in an enhanced antitumour efficacy compared to either agent alone. Pharmacokinetic studies in the mouse following intravenous injection showed that HGS-ETR1 serum concentrations were biphasic with a terminal half-life of 6.9 -8.7 days and a steady-state volume of distribution of approximately 60 ml kg À1 . Clearance was 3.6 -5.7 ml À1 day À1 kg À1 . These data suggest that HGS-ETR1 is a specific and potent antitumour agent with favourable pharmacokinetic characteristics and the potential to provide therapeutic benefit for a broad range of human malignancies.

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Safety and antitumor activity of recombinant soluble Apo2 ligand

Cited by 2,027 publications

References 37 publications

Induction of apoptosis in experimental human B cell lymphomas by conditional TRAIL-expressing T cells

Induction of apoptosis in experimental human B cell lymphomas by conditional TRAIL-expressing T cells

TRAIL activates acid sphingomyelinase via a redox mechanism and releases ceramide to trigger apoptosis

HGS-ETR1, a fully human TRAIL-receptor 1 monoclonal antibody, induces cell death in multiple tumour types in vitro and in vivo

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