Effect of TRA-8 anti-death receptor 5 antibody in combination with chemotherapy in an ex vivo human ovarian cancer model.

Academic Article

Abstract

  • OBJECTIVES: To investigate the cytotoxicity of TRA-8, an antibody that specifically binds death receptor 5, alone and in combination with chemotherapy, using an ex vivo human ovarian cancer model. MATERIALS AND METHODS: Twenty-six ovarian cancer specimens were obtained during ovarian cancer debulking, and tumor slices were prepared with the Krumdieck tissue slicer. The tumor slices were exposed to varying concentrations of TRA-8, carboplatin/paclitaxel, or the combination of TRA-8 and chemotherapy. Using nonlinear modeling, dose-response curves and IC50 values were generated for specimens treated with TRA-8. The additive and synergistic cytotoxic effects of chemotherapy combination with TRA-8 were evaluated in specimens. In addition to adenosine triphosphate viability assays, the treated and untreated slices were assessed by immunohistochemistry to confirm apoptosis induction. RESULTS: Specimens from 13 patients yielded TRA-8-induced IC50 values. Of these specimens, 15% were found to be sensitive to TRA-8-induced cytotoxicity at IC50 doses less than 500 ng/mL. Specimens from 13 patients underwent combination treatment with TRA-8 and carboplatin/paclitaxel. Of these specimens, 77% exhibited additive cytotoxicity in comparison with those treated with either agent alone, whereas 15% exhibited synergistic cytotoxicity. Immunohistochemical analysis of terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling and cleaved caspase 3 staining demonstrated a dose-dependent increase in apoptosis with the combination treatment. CONCLUSIONS: This study demonstrates the efficacy of the death receptor monoclonal antibody TRA-8 in combination with conventional chemotherapy in an ex vivo human ovarian cancer model. This model can be used to assess cytotoxicity of novel agents in combination with chemotherapy in ovarian cancer.
  • Keywords

  • Adenocarcinoma, Aged, Aged, 80 and over, Antibodies, Monoclonal, Antineoplastic Combined Chemotherapy Protocols, Apoptosis, Carboplatin, Carcinoma, Papillary, Combined Modality Therapy, Cystadenocarcinoma, Serous, Dose-Response Relationship, Drug, Drug Synergism, Endometrial Neoplasms, Female, Humans, Immunoenzyme Techniques, In Situ Nick-End Labeling, Inhibitory Concentration 50, Middle Aged, Ovarian Neoplasms, Paclitaxel, Receptors, TNF-Related Apoptosis-Inducing Ligand, Treatment Outcome
  • Digital Object Identifier (doi)

    Pubmed Id

  • 16239657
  • Author List

  • Frederick PJ; Kendrick JE; Straughn JM; Della Manna DL; Oliver PG; Lin H-Y; Grizzle WE; Stockard CR; Alvarez RD; Zhou T
  • Start Page

  • 814
  • End Page

  • 819
  • Volume

  • 19
  • Issue

  • 5