Anti-tumor activity of TRA-8 anti-death receptor 5 (DR5) monoclonal antibody in combination with chemotherapy and radiation therapy in a cervical cancer model.
OBJECTIVE
There is substantial evidence that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) causes apoptosis via activation of death receptors 4 and 5 (DR4 and DR5). We sought to determine the therapeutic potential of TRA-8 (anti-DR5 monoclonal antibody) in combination with chemotherapy and radiation therapy in a cervical cancer model.


METHODS
DR5 expression in 7 human cervical cancer cell lines was analyzed by indirect immunofluorescence using murine TRA-8 in combination with flow cytometry. Cell lines were treated with TRA-8 alone or in combination with cisplatin, topotecan, or radiation, and cytotoxicity assays were performed. Mice were inoculated with ME-180 cancer cells and treated with different combinations of therapy. Animals receiving antibody were injected intraperitoneally with 200 microg of TRA-8. Animals received 9 Gy 60Co radiation divided into 3 fractions and 3 intraperitoneal doses of cisplatin (6 mg/kg) 1 h before radiation. A similar experiment was performed using topotecan (2 mg/kg) as the chemotherapeutic agent.


RESULTS
DR5 was expressed to a varying degree on the cervical cancer cell lines. Combination treatment with TRA-8 and chemotherapy or radiation resulted in synergistic cytotoxicity in vitro. In vivo, combination therapy with TRA-8, cisplatin, and radiation produced tumor growth inhibition that was significantly greater than the other groups. Similar results were seen in combination studies with topotecan.


CONCLUSIONS
These data suggest that DR5 is a good target for activation of the apoptotic pathway. Monoclonal antibodies such as TRA-8 may play an important role in the development of an effective treatment strategy for patients with advanced cervical cancer.
Straughn
J Michael
JM
Division of Gynecologic Oncology, University of Alabama at Birmingham, 619 19th Street South, OHB Room 538, Birmingham, AL 35249, USA. jmstraughn@yahoo.com
Oliver
Patsy G
PG
Zhou
Tong
T
Wang
Wenquan
W
Alvarez
Ronald D
RD
Grizzle
William E
WE
Buchsbaum
Donald J
DJ
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology; D003131:Combined Modality Therapy; D004357:Drug Synergism; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis / Q000276:immunology*; D019772:Topotecan / Q000008:administration & dosage / Q000494:pharmacology; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000532:radiotherapy / Q000628:therapy*; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; C505639:TNFRSF10B protein, human; C505640:Tnfrsf10b protein, mouse; D019772:Topotecan; D002945:Cisplatin