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.

Academic Article

Abstract

  • 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.
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    Keywords

  • Animals, Antibodies, Monoclonal, Antineoplastic Combined Chemotherapy Protocols, Cell Line, Tumor, Cisplatin, Combined Modality Therapy, Drug Synergism, Female, Humans, Mice, Mice, Nude, Receptors, TNF-Related Apoptosis-Inducing Ligand, Receptors, Tumor Necrosis Factor, Topotecan, Uterine Cervical Neoplasms, Xenograft Model Antitumor Assays
  • Digital Object Identifier (doi)

    Author List

  • Straughn JM; Oliver PG; Zhou T; Wang W; Alvarez RD; Grizzle WE; Buchsbaum DJ
  • Start Page

  • 46
  • End Page

  • 54
  • Volume

  • 101
  • Issue

  • 1