Interaction of Insulin-like growth factor receptor I (IGF-IR) with the ligands, insulin-growth factor I and II (IGF-I and IGF-II) has major functions in cell proliferation, transformation and blockade of cell apoptotic functions. It has been reported that numerous tumor cell types overexpress IGF-IR, thus, its blockade could be of importance for anti-cancer therapy. h7C10, a humanized anti-IGF-IR antibody, blocks in vitro IGF-I and IGF-II induced cell proliferation of MCF-7 breast cancer cells. Treatment of nude mice bearing either human breast cancer cells (MCF-7) or non small lung cancer cells (A549) with h7C10, significantly inhibited tumor growth. Overall results indicated that the humanized anti-IGF-IR antibody h7C10 has great potential for cancer therapy. To further elucidate of the mechanism of action of h7C10, we investigated whether it could interfere with vascular endothelial growth factor (VEGF) production. It has previously been reported that IGF-I induces VEGF expression in a variety of tumor cells including MCF-7 cells. In addition, interfering with IGF-IR function with a dominant negative form of IGF-IR abrogated VEGF production both at mRNA and protein levels. In vitro effects of h7C10 on this angiogenic factor was investigated in MCF-7 tumor cell. After incubation of cells with IGF-1, we detected VEGF protein secretion by ELISA. mRNA encoding for VEGF was also up-regulated after IGF-1 activation. VEGF protein production was abolished after cell incubation with h7C10. The inhibition effect was maximal with 10μg/ml of h7C10. Our results indicate that h7C10 blocks IGF-1 induced VEGF production and confirm that the IGF IR system plays an important role in multiple mechanisms that mediate cancer cell growth including regulation of VEGF and angiogenesis.
[Proc Amer Assoc Cancer Res, Volume 47, 2006]