RESUMEN
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. MATERIALS AND 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.