title: Interferon gamma enhances the effectiveness of tumor necrosis factor-related apoptosis-inducing ligand receptor agonists in a xenograft model of Ewing's sarcoma.
abstract: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces selective apoptosis in a variety of tumors, including most cell lines derived from Ewing's sarcoma family of tumors, an aggressive sarcoma that afflicts children and young adults. To determine the in vivo efficacy of TRAIL receptor agonists in Ewing's sarcoma family of tumors, mice with orthotopic xenografts were treated with anti-TRAIL-R2 monoclonal antibody or TRAIL/Apo2L in a model that can identify effects on both primary tumors and metastases. Administration of either agonist slowed tumor growth in 60% of animals and induced durable remissions in 11 to 19% but did not alter the incidence of metastatic disease. Response rates were not improved by concurrent doxorubicin treatment. Cells recovered from both TRAIL receptor agonist-treated and nontreated tumors were found to be resistant to TRAIL-induced death in vitro unless pretreated with interferon (IFN) gamma. This resistance coincided with a selective down-regulation of TRAIL receptor expression on tumor cells. In vivo treatment with IFNgamma increased tumor expression of TRAIL receptors and caspase 8, but did not increase the antitumor effect of TRAIL receptor agonists on primary tumors. However, IFNgamma treatment alone or in combination with a TRAIL receptor agonist significantly decreased the incidence of metastatic disease and the combination of TRAIL receptor agonist therapy with IFNgamma-mediated impressive effects on both primary tumors and metastatic disease. These data demonstrate that in vivo growth favors TRAIL resistance but that TRAIL receptor agonists are active in Ewing's sarcoma family of tumors and that the combination of TRAIL receptor agonists with IFNgamma is a potent regimen in this disease capable of controlling both primary and metastatic tumors.
authors.affiliation: Pediatric Oncology Branch and Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. merchanm@mail.nih.gov
authors.forename: Melinda S
authors.initials: MS
authors.lastname: Merchant
authors.forename: Xuezhong
authors.initials: X
authors.lastname: Yang
authors.forename: Fraia
authors.initials: F
authors.lastname: Melchionda
authors.forename: Maria
authors.initials: M
authors.lastname: Romero
authors.forename: Ruth
authors.initials: R
authors.lastname: Klein
authors.forename: Carol J
authors.initials: CJ
authors.lastname: Thiele
authors.forename: Maria
authors.initials: M
authors.lastname: Tsokos
authors.forename: H Udo
authors.initials: HU
authors.lastname: Kontny
authors.forename: Crystal L
authors.initials: CL
authors.lastname: Mackall
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D006801:Humans; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000494:pharmacology*; D009368:Neoplasm Transplantation; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000819:agonists*; D012512:Sarcoma, Ewing / Q000473:pathology*
chemical_list: D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; C505639:TNFRSF10B protein, human; D007371:Interferon-gamma