title: Insulin-like growth factor I receptor antagonism augments response to chemoradiation therapy in colon cancer cells.
abstract: BACKGROUND
  Colorectal cancer remains one of the most prevalent malignancies in the United States. Improvement in local disease control is seen when 5-fluorouracil (5-FU) is used in combination with pelvic irradiation for rectal adenocarcinoma. The frequent overexpression of insulin-like growth factor I receptor (IGF-I-R) in rectal adenocarcinoma suggests that inhibition of the signal transduction pathway may be a novel approach to enhance tumor response. This investigation seeks to define the role of IGF-I-R antagonism, using monoclonal antibody alpha-IR3, in augmenting cytotoxicity to adjuvant chemoradiation therapy for adenocarcinoma of the rectum.
  
  
  METHODS
  SW 480 colon cancer cells were cultured to semiconfluent conditions with dose titrations performed for 5-FU to determine that the IC(50) (inhibitory concentration of 50% of the cells) was 0.5 microg/ml. The IC(50) for 5-FU was reassessed in the presence of IGF-I. Experimental groups included colon cancer cells combined with 5-FU; 6-MeV external beam radiation (100-500 cGy); and alpha-IR-3.
  
  
  RESULTS
  The addition of 100 ng/ml IGF-I 1 h prior to 5-FU or radiation significantly blunted the expected cytotoxicity, resulting in a 10-fold increase in the IC(50) (from 0.5 to 5 microg/ml). Receptor antagonism using the monoclonal antibody alpha-IR-3 (100-400 ng/ml) produced a dose-dependent increase in cytotoxicity compared with 5-FU alone. The addition of radiation produced synergistic amplification of this response.
  
  
  CONCLUSIONS
  IGF-I-R activation blocks the expected cytotoxic effects of 5-FU and external beam radiation. Receptor antagonism increased the cytotoxic response of chemoradiation therapy. These data suggest the utility of inhibiting IGF-I-R signal transduction in the treatment of rectal adenocarcinoma.
authors.affiliation: Department of Surgery, Tulane University School of Medicine, New Orleans, Louisiana 70118, USA.
authors.forename: E S
authors.initials: ES
authors.lastname: Perer
authors.forename: A K
authors.initials: AK
authors.lastname: Madan
authors.forename: A
authors.initials: A
authors.lastname: Shurin
authors.forename: E
authors.initials: E
authors.lastname: Zakris
authors.forename: K
authors.initials: K
authors.lastname: Romeguera
authors.forename: Y
authors.initials: Y
authors.lastname: Pang
authors.forename: D J
authors.initials: DJ
authors.lastname: Beech
mesh_terms: D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D002455:Cell Division / Q000187:drug effects / Q000528:radiation effects; D003110:Colonic Neoplasms / Q000473:pathology / Q000628:therapy*; D003131:Combined Modality Therapy; D005472:Fluorouracil / Q000494:pharmacology; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000502:physiology; D014407:Tumor Cells, Cultured
chemical_list: D000911:Antibodies, Monoclonal; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; D005472:Fluorouracil