title: The efficacy of IGF-I receptor monoclonal antibody against human gastrointestinal carcinomas is independent of k-ras mutation status.
abstract: OBJECTIVE
  Insulin-like growth factor (IGF)-I receptor (IGF-IR) signaling is required for carcinogenicity and proliferation of gastrointestinal cancers. We have previously shown successful targeting therapy for colorectal, pancreatic, gastric, and esophageal carcinomas using recombinant adenoviruses expressing dominant negative IGF-IR. Mutation in k-ras is one of key factors in gastrointestinal cancers. In this study, we sought to evaluate the effect of a new monoclonal antibody for IGF-IR, figitumumab (CP-751,871), on the progression of human gastrointestinal carcinomas with/without k-ras mutation.
  
  
  METHODS
  We assessed the effect of figitumumab on signal transduction, proliferation, and survival in six gastrointestinal cancer cell lines with/without k-ras mutation, including colorectal and pancreatic adenocarcinoma, esophageal squamous cell carcinoma, and hepatoma. Combination effects of figitumumab and chemotherapy were also studied. Then figitumumab was evaluated in the treatment of xenografts in nude mice.
  
  
  RESULTS
  Figitumumab blocked autophosphorylation of IGF-IR and its downstream signals. The antibody suppressed proliferation and tumorigenicity in all cell lines. Figitumumab inhibited survival by itself and up-regulated chemotherapy (5-FU and gemcitabine) induced apoptosis. Moreover, the combination of this agent and chemotherapy was effective against tumors in mice. The effect of figitumumab was not influenced by the mutation status of k-ras. Figitumumab reduced expression of IGF-IR but not insulin receptor in these xenografted tumors. The drug did not affect murine body weight or blood concentrations of glucose, insulin, IGF binding protein 3, and growth hormone.
  
  
  CONCLUSIONS
  IGF-IR might be a good molecular therapeutic target and figitumumab may thus have therapeutic value in human gastrointestinal malignancies even in the presence of k-ras mutations.
authors.affiliation: First Department of Internal Medicine, Sapporo Medical University, Sapporo, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Ii
authors.forename: Hua
authors.initials: H
authors.lastname: Li
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Adachi
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yamamoto
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Ohashi
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Taniguchi
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Arimura
authors.forename: David P
authors.initials: DP
authors.lastname: Carbone
authors.forename: Kohzoh
authors.initials: K
authors.lastname: Imai
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Shinomura
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018450:Disease Progression; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D011905:Genes, ras; D006801:Humans; D016756:Immunoglobulins, Intravenous; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D017526:Receptor, IGF Type 1 / Q000276:immunology*; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D016756:Immunoglobulins, Intravenous; D017526:Receptor, IGF Type 1; C525021:figitumumab