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

Gynecol Oncol. 2006 Apr;101(1):46-54. doi: 10.1016/j.ygyno.2005.09.053. Epub 2005 Nov 4.


Objectives: 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.

MeSH terms

  • Animals
  • Antibodies, Monoclonal / administration & dosage
  • Antibodies, Monoclonal / immunology
  • Antibodies, Monoclonal / pharmacology*
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Cell Line, Tumor
  • Cisplatin / administration & dosage
  • Cisplatin / pharmacology
  • Combined Modality Therapy
  • Drug Synergism
  • Female
  • Humans
  • Mice
  • Mice, Nude
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • Receptors, Tumor Necrosis Factor / biosynthesis
  • Receptors, Tumor Necrosis Factor / immunology*
  • Topotecan / administration & dosage
  • Topotecan / pharmacology
  • Uterine Cervical Neoplasms / drug therapy
  • Uterine Cervical Neoplasms / immunology
  • Uterine Cervical Neoplasms / radiotherapy
  • Uterine Cervical Neoplasms / therapy*
  • Xenograft Model Antitumor Assays


  • Antibodies, Monoclonal
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • Receptors, Tumor Necrosis Factor
  • TNFRSF10B protein, human
  • Tnfrsf10b protein, mouse
  • Topotecan
  • Cisplatin