| Title | Effect of TRA-8 Anti-Death Receptor 5 Antibody in Combination With Chemotherapy in an Ex Vivo Human Ovarian Cancer Model. | | Author(s) | Frederick PJ, Kendrick JE, Straughn JM, Della Manna DL, Oliver PG, Lin HY, Grizzle WE, Stockard CR, Alvarez RD, Zhou T, Lobuglio AF, Buchsbaum DJ | | Institution | *Division of Gynecologic Oncology, Departments of daggerRadiation Oncology, double daggerMedicine, and section signPathology, Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, AL. | | Source | Int J Gynecol Cancer 2009 Jul; 19(5):814-819. | | 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. | | Language | ENG | | Pub Type(s) | JOURNAL ARTICLE
| | PubMed ID | 19574765 |
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