Effects of genetic blockade of the insulin-like growth factor receptor in human colon cancer cell lines.

Adachi Y, Lee CT, Coffee K, Yamagata N, Ohm JE, Park KH, Dikov MM, Nadaf SR, Arteaga CL, Carbone DP
Gastroenterology. 2002 123 (4): 1191-204

PMID: 12360481 · DOI:10.1053/gast.2002.36023

BACKGROUND & AIMS - Insulin-like growth factor (IGF)-I receptor (IGF-Ir) signaling is required for maintenance of growth and tumorigenicity of several tumor types. We have previously shown successful therapy in a lung cancer xenograft model using an adenovirus expressing antisense IGF-Ir. In this study, we sought to better dissect the mechanism and develop potentially more effective IGF-Ir-targeted therapeutics by developing and testing tetracycline-regulated and recombinant adenoviruses expressing dominant negative receptors.

METHODS - Truncated IGF-I receptors (IGF-Ir/tf; 482 and 950 amino acids long, respectively [IGF-Ir/482st and IGF-Ir/950st]) were cloned into tetracycline-regulated vectors and recombinant adenoviruses and then studied in colorectal cancer cells. We assessed the effect of IGF-Ir/tf on signaling blockade, colony formation, stress response (serum starvation and heat), chemotherapy-induced apoptosis, and in vivo therapeutic efficacy in xenografts.

RESULTS - Activation of IGF-Ir/tf expression by withdrawal of tetracycline suppressed tumorigenicity both in vitro and in vivo and up-regulated stressor-induced apoptosis. It effectively blocked both IGF-I- and IGF-II-induced activation of Akt-1. IGF-Ir/tf expression increased chemotherapy-induced apoptosis, and this combination therapy was very effective against tumors in mice. These findings were confirmed in a therapy model against established tumors using adenoviruses expressing IGF-Ir/tf. Moreover, IGF-Ir/482st was more effective than IGF-Ir/950st because of its bystander effect.

CONCLUSIONS - Anti-tumor activity of IGF-Ir/tf is mediated through inhibition of Akt-1 and enhances the efficacy of chemotherapy. Adenovirus IGF-Ir/482st may be a useful anticancer therapeutic for colorectal carcinoma.

MeSH Terms (25)

Adenoviridae Animals Anti-Bacterial Agents Antineoplastic Agents Apoptosis Blood Proteins Carcinogenicity Tests Cell Division Colonic Neoplasms DNA, Complementary Female Gene Expression Regulation, Neoplastic Genetic Therapy Heat-Shock Response HT29 Cells Humans Mice Mice, Nude Protein-Serine-Threonine Kinases Proto-Oncogene Proteins Proto-Oncogene Proteins c-akt Receptor, IGF Type 1 Signal Transduction Tetracycline Transfection

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