Inhibition of the type 1 insulin-like growth factor receptor expression and signaling: Novel strategies for antimetastatic therapy

The receptor fur the type 1 insulin-like growth factor (IGF-1R) plays a cri tical role in the acquisition of the malignant phenotype. Using a highly me tastatic murine lung carcinoma model, it was demonstrated that this recepto r regulates several cellular functions that can impact on the metastatic po tential of the cells, including cellular proliferation, anchorage-independe nt growth, cell migration, and invasion. The tumor model was used to develo p several strategies for altering receptor expression and function as means of abrogating the metastatic potential of the cells. They include stable e xpression in the turner cells of IGF-1R antisense RNA and dominant negative receptor mutants in which tyrosines in the kinase domain were substituted with phenylalanine. In addition, a novel strategy was used based on alterin g post ligand-binding receptor turnover. This led to inhibition of receptor re-expression and signaling and resulted in increased tumor cell apoptosis . When combined with the development of viral vectors designed to deliver g enetic information with high efficiency, these strategies could form the ba sis for development of highly specific, antimetastatic therapy in tumors wi th known IGF-IR involvement. BIOCHEM PHARMACOL 60;8:1101-1107, 2000. (C) 20 00 Elsevier Science Inc.