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Effect of TRA-8 Anti-Death Receptor 5 Antibody in Combination With Chemotherapy in an Ex Vivo Human Ovarian Cancer Model
  1. Peter J. Frederick, MD*,
  2. James E. Kendrick, MD*,
  3. Jr. J. Michael Straughn, MD*,
  4. Debbie L. Della Manna, MS,
  5. Patsy G. Oliver, PhD,
  6. Hui-Yi Lin, PhD,
  7. William E. Grizzle, MD§,
  8. Cecil R. Stockard, MS§,
  9. Ronald D. Alvarez, MD*,
  10. Tong Zhou, MD,
  11. Albert F. Lobuglio, MD and
  12. Donald J. Buchsbaum, PhD
  1. *Division of Gynecologic Oncology, Departments of
  2. Radiation Oncology,
  3. Medicine, and
  4. §Pathology, Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, AL.
  1. Address correspondence and reprint requests to Peter J. Frederick, MD, Division of Gynecologic Oncology, Comprehensive Cancer Center, The University of Alabama at Birmingham, 619 19th St South, OHB 538, Birmingham, 35249 AL.

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.

  • TRA-8
  • Death receptor 5
  • Ovarian cancer
  • TRAIL
  • Monoclonal antibody

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Footnotes

  • Conflict of Interest: Drs Zhou, LoBuglio, and Buchsbaum have intellectual property related to the TRA-8 anti-DR5 antibody.

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