title: Targeting of insulin-like growth factor-I receptor with a monoclonal antibody inhibits growth of hepatic metastases from human colon carcinoma in mice.
abstract: BACKGROUND
  Colorectal carcinomas (CRC) express high levels of insulin-like growth factor-I/II (IGF-I/II) and the receptor (IGF-IR). We hypothesized that selective inhibition of IGF-IR would inhibit hepatic growth of human CRC in mice.
  
  
  METHODS
  Human CRC cells were treated in vitro with anti-IGF-IR monoclonal antibody (MoAB) with and without oxaliplatin to assess cytotoxicity. The effect of anti-IGF-IR MoAB on IGF-I-induced vascular endothelial growth factor (VEGF) production in human CRC cells was assessed by Northern blot and ELISA. We injected human CRC cells intrahepatically in nude mice, and then administered anti-IGF-IR MoAB with and without oxaliplatin. We delayed treatment in one group until large hepatic tumors were present. We assessed tumors for apoptosis, proliferation, and angiogenesis.
  
  
  RESULTS
  Anti-IGF-IR MoAB and oxaliplatin inhibited CRC cell growth in vitro and combination treatment was even more effective. IGF-I stimulation of CRC cells resulted in significant upregulation of VEGF and this was completely inhibited by pretreatment with anti-IGF-IR MoAB. Anti-IGF-IR MoAB significantly inhibited hepatic growth of tumors in mice. Anti-IGF-IR MoAB plus oxaliplatin led to a significantly greater inhibition of tumor growth. Anti-IGF-IR MoAB plus oxaliplatin was just as effective at inhibiting growth of larger, more advanced liver tumors. Anti-IGF-IR MoAB, alone and in combination with oxaliplatin, led to a significant increase in tumor cell apoptosis, and a significant inhibition of tumor cell proliferation and angiogenesis.
  
  
  CONCLUSIONS
  These findings suggest that IGF-IR is a potential target for therapy in patients with advanced CRC.
authors.affiliation: Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA.
authors.forename: Todd W
authors.initials: TW
authors.lastname: Bauer
authors.forename: Fan
authors.initials: F
authors.lastname: Fan
authors.forename: Wenbiao
authors.initials: W
authors.lastname: Liu
authors.forename: Ernest R
authors.initials: ER
authors.lastname: Camp
authors.forename: Anthony
authors.initials: A
authors.lastname: Yang
authors.forename: Ray J
authors.initials: RJ
authors.lastname: Somcio
authors.forename: Corazon D
authors.initials: CD
authors.lastname: Bucana
authors.forename: Rajeeva
authors.initials: R
authors.lastname: Singh
authors.forename: Lee M
authors.initials: LM
authors.lastname: Ellis
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015152:Blotting, Northern; D002455:Cell Division / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects*; D015179:Colorectal Neoplasms / Q000473:pathology*; D004797:Enzyme-Linked Immunosorbent Assay; D019073:HT29 Cells / Q000187:drug effects / Q000473:pathology / Q000637:transplantation; D006801:Humans; D020287:In Situ Nick-End Labeling; D066298:In Vitro Techniques; D008114:Liver Neoplasms, Experimental / Q000473:pathology / Q000556:secondary*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000473:pathology; D009944:Organoplatinum Compounds / Q000494:pharmacology; D000077150:Oxaliplatin; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D042461:Vascular Endothelial Growth Factor A; D000077150:Oxaliplatin; D017526:Receptor, IGF Type 1