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Activity of selective fully human agonistic antibodies to the TRAIL death receptors TRAIL-R1 and TRAIL-R2 in primary and cultured lymphoma cells: induction of apoptosis and enhancement of doxorubicin- and bortezomib-induced cell death
- Source :
- British journal of haematology. 130(4)
- Publication Year :
- 2005
-
Abstract
- Summary Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo2L) is a death protein that preferentially kills tumour cells while sparing normal cells. TRAIL has four exclusive receptors, two of which (TRAIL-R1, TRAIL-R2) are death receptors. Both TRAIL/Apo2L and agonistic antibodies to the TRAIL death receptors are currently being explored for cancer therapy. Although the activity of TRAIL/Apo2L in a variety of haematological malignancies has been examined, the activity of anti-TRAIL receptor agonistic antibodies in primary and cultured lymphoma cells has not. Using two fully human selective agonistic monoclonal antibodies to the TRAIL death receptors TRAIL-R1 (HGS-ETR1) and TRAIL-R2 (HGS-ETR2) this study demonstrated that both monoclonal antibodies activated caspase-8 and induced cell death in five of nine human lymphoma cell lines, and induced >10% cell death in 67% and 70%, respectively, of 27 primary lymphoma cells, and >20% cell death in at least one-thirds of the samples. HGS-ETR1 and HGS-ETR2 demonstrated comparable activity in the fresh tumour samples, which was independent of TRAIL receptor surface expression, Bax, cFLIP, or procaspase-8 expression, or exposure to prior therapy. Furthermore, both antibodies enhanced the killing effect of doxorubicin and bortezomib. Our data demonstrate that HGS-ETR1 and HGS-ETR2 monoclonal antibodies can induce cell death in a variety of cultured and primary lymphoma cells, and may have therapeutic value in lymphoma.
- Subjects :
- Programmed cell death
Lymphoma
medicine.drug_class
Lexatumumab
Fluorescent Antibody Technique
Antineoplastic Agents
Apoptosis
Monoclonal antibody
Receptors, Tumor Necrosis Factor
Statistics, Nonparametric
Bortezomib
Cell Line, Tumor
medicine
Tumor Cells, Cultured
Humans
Receptor
Cell Proliferation
Analysis of Variance
biology
Antibodies, Monoclonal
Drug Synergism
Hematology
Boronic Acids
Receptors, TNF-Related Apoptosis-Inducing Ligand
Doxorubicin
Pyrazines
Immunology
biology.protein
Cancer research
Antibody
Mapatumumab
medicine.drug
Subjects
Details
- ISSN :
- 00071048
- Volume :
- 130
- Issue :
- 4
- Database :
- OpenAIRE
- Journal :
- British journal of haematology
- Accession number :
- edsair.doi.dedup.....24bb6e935954d3d6dded8eff350add5e