Monoclonal antibody to tumor necrosis factor-related apoptosis-inducing ligand receptor 2 (TRAIL-R2) induces apoptosis in primary renal cell carcinoma cells in vitro and inhibits tumor growth in vivo.

Abstract

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) triggers apoptosis in a variety of tumor cells through two of its receptors: TRAIL-R1 and TRAIL-R2. We investigate the susceptibility of human renal cell carcinoma (RCC) cells to TRM-1 and HGS-ETR2, 2 human monoclonal agonistic antibodies specific for TRAIL-R1 and TRAIL-R2, respectively. HGS-ETR2 effectively induced apoptotic cell death in 10 of 11 cell cultures, including 2 human RCC cell lines and 9 human primary RCC cell cultures, with a more pronounced effect after preincubation with anti-human IgG Fc. In contrast, TRM-1 was effective in only 1 primary RCC cell culture. The increased effectiveness of HGS-ETR2 for inducing cell death might have been affected by differences in the cell-surface expression of the 2 TRAIL receptors, namely that TRAIL-R2 but not TRAIL-R1 was frequently expressed in most of the RCC cells tested. The activities of caspase-9, -8, -6, and -3 were increased with HGS-ETR2-induced apoptosis, and cell death could be blocked by specific caspase inhibitors for caspase-9, -8, and -3, and the general caspase inhibitor. In vivo administration of HGS-ETR2 with or without cross-linker significantly suppressed tumor growth of subcutaneously inoculated human RCC xenografts in immunodeficient mice. These results suggest the potential utility of TRAIL-R2 antibody as a novel therapeutic agent in RCC.

• Authors: Y Zeng, X X Wu, M Fiscella, O Shimada, R Humphreys, V Albert, Y Kakehi
• Journal: International journal of oncology (Int J Oncol) Vol. 28 Issue 2 Pg. 421-30 (Feb 2006) ISSN: 1019-6439 [Print] Greece
• PMID: 16391797 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Caspase Inhibitors
• Enzyme Inhibitors
• Receptors, TNF-Related Apoptosis-Inducing Ligand
• Receptors, Tumor Necrosis Factor
• TNF-Related Apoptosis-Inducing Ligand
• TNFRSF10A protein, human
• lexatumumab
• Caspases

Topics

• Animals
• Antibodies, Monoclonal (administration & dosage, pharmacology)
• Apoptosis (immunology)
• Carcinoma, Renal Cell (pathology, prevention & control)
• Caspase Inhibitors
• Caspases (metabolism)
• Cell Culture Techniques
• Cell Line, Tumor
• Cell Membrane (metabolism)
• Cell Survival
• Enzyme Inhibitors (pharmacology)
• Humans
• Kidney Neoplasms (pathology, prevention & control)
• Male
• Mice
• Mice, Nude
• Mice, SCID
• Receptors, TNF-Related Apoptosis-Inducing Ligand (biosynthesis, immunology)
• Receptors, Tumor Necrosis Factor (immunology, metabolism)
• TNF-Related Apoptosis-Inducing Ligand (pharmacology)
• Xenograft Model Antitumor Assays