Differential hepatocyte toxicity of recombinant Apo2L/TRAIL versions

Lawrence, David A.; Shahrokh, Zahra; Marsters, Scot A.; Achilles, K.; Shih, Danny; Mounho, Barbara; Hillan, Kenneth J.; Tótpál, Klára; DeForge, Laura; Schow, Peter; Hooley, Jeff; Sherwood, Steve; Pai, Roger; Leung, Susan W.S.; Khan, Lolo; Gliniak, Brian; Bussiere, Jeanine L.; Smith, Craig A.; Strom, Stephen S.; Kelley, Sean K.; Fox, Judith A.; Thomas, Deborah A.; Ashkenazi, Avi

doi:10.1038/86397

Cited by 659 publications

(555 citation statements)

References 15 publications

Supporting

Mentioning

540

Contrasting

Unclassified

Order By: Relevance

“…In this context, cultured human hepatocytes or human primary epithelial cells were recently reported to undergo apoptosis in response to recombinant TRAIL, raising concerns of the potential toxicity of TRAIL to normal tissue in vivo (Jo et al, 2000;Nesterov et al, 2002). However, this inconvenience may be attributed to problems in preparation of the respective recombinant TRAIL used in these particular studies (Lawrence et al, 2001), since multiple other reports including our study did not detect the unspecific toxic side effects in vivo (Griffith and Broghammer, 2001;Kagawa et al, 2001;Mohr et al, 2003). Thus, mice receiving switched on Jurkat-TRAIL cells looked healthy, behaved normal and survived due to the benefit of reduced tumour growth.…”

Section: Discussionmentioning

confidence: 99%

“…Surprisingly, previous investigators have reported the toxic effects of TRAIL also on normal primary human cells, including hepatocytes (Jo et al, 2000), keratinocytes (Leverkus et al, 2003) and endothelial cells (Li et al, 2003). The basis of this difference is unclear, but could result from the methods used to assess cell death or problems in preparation of the respective recombinant TRAIL used in these particular studies (Lawrence et al, 2001). Also, primary keratinocytes are relatively resistant and become first sensitive by inhibition of the proteasome (Leverkus et al, 2003).…”

mentioning

confidence: 99%

See 1 more Smart Citation

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

et al. 2003

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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

et al. 2003

View full text Add to dashboard Cite

show abstract

“…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).…”

mentioning

confidence: 99%

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

View full text Add to dashboard Cite

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.

show abstract

“…Among the four receptors, two DRs (death receptors DR4/TRAIL-R1 and DR5/TRAIL-R2) present an intracellular death domain that, upon TRAIL binding, recruits adaptor proteins (FADD (Fas-associated death domain)) and initiator caspases (procaspases-8/10), thereby transducing the apoptotic signal by activating the caspase cascade via the extrinsic pathway (Figure 2b). In some cells, TRAIL will also operate by activating the intrinsic pathway, crosstalk mediated by the action of Bid (Figure 2b However, later reports indicated that this toxic effect, observed under in vitro culturing conditions, might result from the use of tagged-TRAIL (histidine, FLAG or leucine-tagged TRAIL), whereas the recombinant untagged version of the cytokine was nontoxic on normal cells (Lawrence et al, 2001;Qin et al, 2001). Furthermore, recent studies have shown that whereas the tagged versions of TRAIL might result in toxicity on primary human hepatocytes in vitro, the same compounds displayed very modest toxic effect on hepatic explants obtained from healthy donors, indicating that the use of primary human hepatocytes as model for analyzing toxicity effects might not be the most suitable (Volkmann et al, 2007).…”

Section: Novel Paradigms For Cancer Therapy V Pavet Et Almentioning

confidence: 99%

Towards novel paradigms for cancer therapy

et al. 2010

View full text Add to dashboard Cite

Cancer is a complex progressive multistep disorder that results from the accumulation of genetic and epigenetic abnormalities, which lead to the transformation of normal cells into malignant derivatives. Despite enormous progress in the understanding of cancer biology including the decryption of multiple regulatory networks governing cell growth and death, and despite the possibility of analyzing (epi)genetic deregulation at the genome-wide scale, cancertargeted therapy is still the exception. In fact, to date there are still far too few examples of therapies leading to cure; treatment-derived toxicity is a major issue, and cancer remains to be one of the largest causes of death worldwide. The purpose of this review is to discuss the state of the art of cancer therapy with respect to the key issue of any treatment, namely its target selectivity. Therefore, we recapitulate and discuss current concepts and therapies targeting tumorspecific features, including oncofusion proteins, aberrant kinase activities and epigenetic tumor makeup. We analyze strategies designed to induce tumor-selective death such as the use of oncolytic virus, tumoricidal proteins (NS1, Eorf4, apoptin, HAMLET (human a-lactalbumin made lethal to tumor cells)) and activation of signaling pathways involved in tumor surveillance. We emphasize the potential of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) pathway, an essential component of the evolutionary developed defense systems that eradicate malignant cells. Finally, we discuss the necessity of targeting tumor-initiating cells (TICs) to avoid relapse and increase the chances of complete remission, and describe emerging concepts that might provide novel avenues for cancer therapy.

show abstract

Differential hepatocyte toxicity of recombinant Apo2L/TRAIL versions

Cited by 659 publications

References 15 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

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

Towards novel paradigms for cancer therapy

Contact Info

Product

Resources

About