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.