Lexatumumab (TRAIL-receptor 2 mAb) induces expression of DR5 and promotes apoptosis in primary and metastatic renal cell carcinoma in a mouse orthotopic model.

Abstract

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in a variety of tumorigenic and transformed cell lines but not in many normal cells. Hence, TRAIL-agonist compounds have the potential of being excellent cancer therapeutic agents with minimal cytotoxicity. Here, we examine the efficacy of the TRAIL-receptor 2 agonist, lexatumumab (Human Genome Sciences, Inc., Rockville, MD), and identify molecular pathways that differentiate between lexatumumab-sensitive and lexatumumab-resistance renal cancer cells. In an orthotopic metastatic mouse model, we first demonstrate that lexatumumab was effective in reducing the tumor burden of primary and metastatic lexatumumab-sensitive xenografts. We demonstrate that lexatumumab-sensitive cells were capable of triggering both the extrinsic and the intrinsic apoptotic pathways as demonstrated by caspase 8 and caspase 9 activations, respectively, after treatment with lexatumumab. In addition, expression of c-FLIP(L) protein, an important regulator of TRAIL-induced apoptosis, decreased, while expression of the TRAIL-receptor 2, DR5, increased. This study serves as a pre-clinical model for using TRAIL-like therapies for patients with advanced RCC.

• Authors: Liang Zhang, Xiaoping Zhang, Glen W Barrisford, Aria F Olumi
• Journal: Cancer letters (Cancer Lett) Vol. 251 Issue 1 Pg. 146-57 (Jun 18 2007) ISSN: 0304-3835 [Print] Ireland
• PMID: 17184908 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antibodies, Monoclonal
• CASP8 and FADD-Like Apoptosis Regulating Protein
• Receptors, TNF-Related Apoptosis-Inducing Ligand
• lexatumumab

Topics

• Animals
• Antibodies, Monoclonal (immunology, pharmacology)
• Apoptosis (drug effects)
• Blotting, Western
• CASP8 and FADD-Like Apoptosis Regulating Protein (metabolism)
• Carcinoma, Renal Cell (pathology, prevention & control, secondary)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Dose-Response Relationship, Drug
• Humans
• Immunohistochemistry
• Kidney Neoplasms (metabolism, pathology, prevention & control)
• Mice
• Mice, Nude
• Receptors, TNF-Related Apoptosis-Inducing Ligand (immunology, metabolism)
• Tumor Burden (drug effects)
• Xenograft Model Antitumor Assays