PT  - JOURNAL ARTICLE
AU  - Frederick, Peter J.
AU  - Kendrick, James E.
AU  - Straughn, J. Michael
AU  - Della Manna, Debbie L.
AU  - Oliver, Patsy G.
AU  - Lin, Hui-Yi
AU  - Grizzle, William E.
AU  - Stockard, Cecil R.
AU  - Alvarez, Ronald D.
AU  - Zhou, Tong
AU  - Lobuglio, Albert F.
AU  - Buchsbaum, Donald J.
TI  - Effect of TRA-8 Anti-Death Receptor 5 Antibody in Combination With Chemotherapy in an Ex Vivo Human Ovarian Cancer Model
AID  - 10.1111/IGC.0b013e3181a2a003
DP  - 2009 Jul 01
TA  - International Journal of Gynecologic Cancer
PG  - 814-819--814-819
VI  - 19
IP  - 5
4099  - http://ijgc.bmj.com/content/19/5/814-819.short
4100  - http://ijgc.bmj.com/content/19/5/814-819.full
SO  - Int J Gynecol Cancer2009 Jul 01; 19
AB  - 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.