Transl Res. 2009 Jun;153(6):275-82. Epub 2009 Mar 14.
Novel insulin-like growth factor-methotrexate covalent conjugate inhibits tumor growth in vivo at lower dosage than methotrexate alone.
McTavish H, Griffin RJ, Terai K, Dudek AZ.
IGF Oncology, LLC, Saint Paul, MN 55110, USA. hmctavish@IGFOncology.com
The insulin-like growth factor receptor is overexpressed on many types of cancer cells and has been implicated in metastasis and resistance to apoptosis. We report here the development of a novel covalent conjugate that contains the antifolate drug methotrexate coupled to an engineered variant of insulin-like growth factor-1 (IGF-1), long-R3-IGF-1, which was designed to target methotrexate to tumor cells that overexpress the membrane IGF-1 receptor. The IGF-methotrexate conjugate was found to contain at least 4 methotrexate molecules per IGF-1 protein. The IGF-methotrexate conjugate bound to MCF7 breast cancer cells with greater than 3.3-fold higher affinity than unconjugated long-R3-IGF-1 in a competition binding assay against radiolabeled wild-type IGF-1. Compared with free methotrexate, the IGF-methotrexate conjugate required slightly higher concentrations to inhibit the in vitro growth of the human prostate cancer cell line LNCaP. In vivo, however, in a mouse xenograft model using LNCaP cells, the IGF-methotrexate conjugate was more effective than free methotrexate even at a 6.25-fold lower molar dosage. Similarly, MCF7 xenografts were inhibited more effectively by the IGF-methotrexate conjugate than free methotrexate, even at a 4-fold lower molar dosage. Our results suggest that the targeting of the IGF receptor on tumor cells and tumor-related tissues with IGF-chemotherapy conjugates may substantially increase the specific drug localization and therapeutic effect in the tumor.