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


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.
Frederick
Peter J
PJ
Division of Gynecologic Oncology, Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, AL, USA.
Kendrick
James E
JE
Straughn
J Michael
JM
Della Manna
Debbie L
DL
Oliver
Patsy G
PG
Lin
Hui-Yi
HY
Grizzle
William E
WE
Stockard
Cecil R
CR
Alvarez
Ronald D
RD
Zhou
Tong
T
LoBuglio
Albert F
AF
Buchsbaum
Donald J
DJ
D000230:Adenocarcinoma / Q000276:immunology / Q000473:pathology / Q000628:therapy; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D016190:Carboplatin / Q000008:administration & dosage; D002291:Carcinoma, Papillary / Q000276:immunology / Q000473:pathology / Q000628:therapy; D003131:Combined Modality Therapy; D018284:Cystadenocarcinoma, Serous / Q000276:immunology / Q000473:pathology / Q000628:therapy; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D016889:Endometrial Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D020287:In Situ Nick-End Labeling; D020128:Inhibitory Concentration 50; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000276:immunology / Q000473:pathology* / Q000628:therapy*; D017239:Paclitaxel / Q000008:administration & dosage; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000276:immunology*; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D016190:Carboplatin; D017239:Paclitaxel