title: Anti-tumor activity of an anti-DR5 monoclonal antibody, TRA-8, in combination with taxane/platinum-based chemotherapy in an ovarian cancer model.
abstract: OBJECTIVE
  Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) mediates apoptosis via binding to death receptors and enhances the anti-tumor effect of conventional cancer therapies. We evaluated the efficacy of TRA-8, an agonistic antibody to DR5, combined with docetaxel and carboplatin in vitro in an intraperitoneal (IP) ovarian cancer model.
  
  
  METHODS
  Luciferase positive ES2 cells (ES2H) were treated in 96 well plates with TRA-8, carboplatin, docetaxel, and combination therapy. Cell viability was assessed using ATP-lite assay. Apoptosis was confirmed via Western blot analysis. ES2H cells were injected IP into female athymic nude mice. Animals were sorted based on bioluminescent signal with the following treatments: 1) untreated; 2) TRA-8 alone; 3) docetaxel+carboplatin; and 4) docetaxel+carboplatin+TRA-8. Animals receiving TRA-8 antibody were injected IP with 200 μg of TRA-8 twice weekly until death. Animals receiving docetaxel+carboplatin were injected IP with 5mg/kg and 15 mg/kg respectively every 3 weeks until death. Animals were assessed for tumor burden using bioluminescence imaging and overall survival.
  
  
  RESULTS
  Combination therapy reduced viability of ES2H cells in vitro over single agent therapy. Tumor burden was lowest in the chemotherapy+TRA-8 group at days 23 (p<0.001) and 30 (p = 0.04). Mean survival was greatest in the chemotherapy+TRA-8 group (41 days) compared to the chemotherapy only group (34 days) and control group (27 days) as determined by Kaplan-Meier analysis (p<0.001).
  
  
  CONCLUSIONS
  Conventional chemotherapy combined with TRA-8 reduced cell-viability via activation of apoptotic pathways, reduced tumor burden and improved survival in this ovarian cancer model.
authors.affiliation: Division of Gynecologic Oncology, University of Alabama at Birmingham, Birmingham, AL 35249, USA. ksbevis@gmail.com
authors.forename: Kerri S
authors.initials: KS
authors.lastname: Bevis
authors.forename: Lacey R
authors.initials: LR
authors.lastname: McNally
authors.forename: Jeffery C
authors.initials: JC
authors.lastname: Sellers
authors.forename: Deborah
authors.initials: D
authors.lastname: Della Manna
authors.forename: Angelina
authors.initials: A
authors.lastname: Londoño Joshi
authors.forename: Hope
authors.initials: H
authors.lastname: Amm
authors.forename: J Michael
authors.initials: JM
authors.lastname: Straughn
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Buchsbaum
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D015153:Blotting, Western; D016190:Carboplatin / Q000008:administration & dosage; D045744:Cell Line, Tumor; D000077143:Docetaxel; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D051379:Mice; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000276:immunology; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000096:biosynthesis / Q000276:immunology*; D043823:Taxoids / Q000008:administration & dosage; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D043823:Taxoids; D000077143:Docetaxel; D016190:Carboplatin