title: Combination of the pro-apoptotic TRAIL-receptor antibody mapatumumab with ionizing radiation strongly increases long-term tumor control under ambient and hypoxic conditions.
abstract: OBJECTIVE
  Mapatumumab, an agonistic tumor necrosis factor-related apoptosis inducing ligand-receptor antibody, exerts highly synergistic apoptotic effects in vitro and in short-term growth delay assays when combined with irradiation. Because it remained unclear in how far these effects influence local tumor control, long-term experiments using a colorectal xenograft model were undertaken.
  
  
  METHODS
  Experiments were performed with irradiation (5 x 3 Gy, d1-5) and mapatumumab (10 mg/kg) in Colo205-xenograft-bearing NMRI (nu/nu) nude mice. Graded top up doses were delivered on the tumor-bearing hind leg under ambient and hypoxic conditions; follow-up was 270 days. Growth delay and local tumor control were end points of the study. Statistical analysis of the experiments included calculation of tumor regrowth and local tumor control.
  
  
  RESULTS
  After combined treatment, a pronounced tumor regrowth-delay was observed when compared with irradiation alone. Long-term experiments revealed a highly significant increase in local tumor control for ambient (p = 0.00076) and hypoxic treatment (p = 0.000069).
  
  
  CONCLUSIONS
  The present data demonstrate for the first time that combination of a pro-apoptotic antibody with irradiation results in evidently reduced tumor regrowth times and subsequently highly increased local tumor control under normoxic and hypoxic conditions in a xenograft mouse model.
authors.affiliation: Department of Radiation Oncology, CCC Tübingen, University of Tübingen, Tübingen, Germany.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Marini
authors.forename: Wilfried
authors.initials: W
authors.lastname: Budach
authors.forename: Maximilian
authors.initials: M
authors.lastname: Niyazi
authors.forename: Dorothea
authors.initials: D
authors.lastname: Junginger
authors.forename: Stefan
authors.initials: S
authors.lastname: Stickl
authors.forename: Verena
authors.initials: V
authors.lastname: Jendrossek
authors.forename: Claus
authors.initials: C
authors.lastname: Belka
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000532:radiotherapy; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D017209:Apoptosis; D015687:Cell Hypoxia; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000532:radiotherapy; D003131:Combined Modality Therapy / Q000379:methods; D019583:Dose Fractionation, Radiation; D004307:Dose-Response Relationship, Radiation; D051379:Mice; D008819:Mice, Nude; D009364:Neoplasm Recurrence, Local / Q000517:prevention & control*; D011836:Radiation Tolerance; D011897:Random Allocation; D012044:Regression Analysis; D013997:Time Factors; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C507357:mapatumumab