title: TRA-8 anti-DR5 monoclonal antibody and gemcitabine induce apoptosis and inhibit radiologically validated orthotopic pancreatic tumor growth.
abstract: OBJECTIVE
  To evaluate agonistic TRA-8 monoclonal antibody to human death receptor 5 (DR5) and gemcitabine in vitro and in an orthotopic pancreatic cancer model.
  
  
  METHODS
  Pancreatic cancer cell lines were screened for DR5 expression, cytotoxicity, and apoptosis induced by TRA-8, gemcitabine, or gemcitabine and TRA-8. An orthotopic model of pancreatic cancer was established in severe combined immunodeficient mice. Mice were treated with TRA-8, gemcitabine, or a combination for one or two cycles of therapy. Tumor growth (ultrasound) and survival were analyzed.
  
  
  RESULTS
  All five pancreatic cancer cell lines showed DR5 protein expression and varying sensitivity to TRA-8-mediated cytotoxicity. MIA PaCa-2 cells were very sensitive to TRA-8, moderately resistant to gemcitabine, with additive cytotoxicity to the combination. S2-VP10 cells were resistant to TRA-8 and sensitive to gemcitabine with synergistic sensitivity to the combination. Combination treatment in vitro produced enhanced caspase-3 and caspase-8 activation. A single cycle of therapy produced comparable efficacy for single-agent TRA-8 and the combination of TRA-8 and gemcitabine, with significant reduction in tumor size and prolonged survival compared with gemcitabine alone or control animals. With two cycles of therapy, TRA-8 and combination therapy produced enhanced inhibition of tumor growth compared with single-agent gemcitabine or untreated animals. However, the combination regimen showed enhanced survival as compared with single-agent TRA-8.
  
  
  CONCLUSIONS
  Pancreatic cancer cell lines express varying levels of DR5 and differ in their sensitivity to TRA-8 and gemcitabine-induced cytotoxicity. TRA-8 with two cycles of gemcitabine therapy produced the best overall survival.
authors: Departments of Surgery, University of Alabama at Birmingham, 1530 3rd Avenue South, Wallace Tumor Institute 674, Birmingham, AL 35294-6832, USA.
authors: Leo Christopher
authors: LC
authors: Derosier
authors: Selwyn M
authors: SM
authors: Vickers
authors: Kurt R
authors: KR
authors: Zinn
authors: Zhi
authors: Z
authors: Huang
authors: Wenquan
authors: W
authors: Wang
authors: William E
authors: WE
authors: Grizzle
authors: Jeffrey
authors: J
authors: Sellers
authors: Cecil R
authors: CR
authors: Stockard
authors: Tong
authors: T
authors: Zhou
authors: Patsy G
authors: PG
authors: Oliver
authors: Pablo
authors: P
authors: Arnoletti
authors: Albert F
authors: AF
authors: Lobuglio
authors: Donald J
authors: DJ
authors: Buchsbaum
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002455:Cell Division; D045744:Cell Line, Tumor; D002470:Cell Survival; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D051379:Mice; D016513:Mice, SCID; D010190:Pancreatic Neoplasms / Q000000981:diagnostic imaging / Q000276:immunology / Q000473:pathology*; D011859:Radiography; D000093542:Gemcitabine
chemical_list: D000911:Antibodies, Monoclonal; D003841:Deoxycytidine; D000093542:Gemcitabine