The receptor for the type I insulin-like growth factor (IGF-IR) plays a critical sellckchem role in malignant progression and has been identified as a determinant of the metastatic potential to several organ sites, particularly the lymph nodes and the liver.2,3,4,5,6,7,8 A recent study identified IGF-IR as a risk factor for liver metastasis in colorectal carcinoma patients.9 Clinical and experimental studies have collectively identified the IGF-IR as a target for anticancer therapy (reviewed in ref. 8) and several inhibitors including anti-IGF-IR antibodies and kinase inhibitors have advanced into clinical trials.7,8,10 As in the case of other receptor-targeted therapies (e.g.

, the epidermal growth factor receptor system), the clinical utility of IGF-IR inhibitors will ultimately be determined by parameters such as specificity, mechanism of target inhibition, pharmacokinetics, toxicity, bioavailability, and the ability of the targeted tumor cells to resist treatment through alternate survival pathway.11,12,13 The IGF-IR is synthesized as a polypeptide chain of 1,367 amino acids that is glycosylated and proteolytically cleaved into ��- and ��- subunits that dimerize to form a heterotetrameric receptor tyrosine kinase consisting of two 130�C135 kda ��- and two 90�C95 kda �� chains, with several ���C�� and ���C�� disulfide bridges.14 The ligand binding domain is on the extracellular �� subunits. The �� subunits consist each of an extracellular portion linked to the �� subunit through disulfide bonds, a transmembrane domain and a cytoplasmic portion with a kinase domain and several critical tyrosines and serines involved in the transmission of ligand-induced signals.

15,16,17 The IGF-IR ligands include three structurally homologous peptides, IGF-I and IGF-II and insulin, but the receptor binds IGF-I with the highest affinity.8,17 There is a high degree of homology between human and mouse IGF-I (97% overall homology) and IGF-IR (96% overall). Site directed mutagenesis used to map the IGF-I binding site identified seven amino acid residues critical for receptor binding that are fully conserved between the human and mouse IGF-I. GSK-3 There is also a 100% homology between the human and mouse ligand-binding domains of the receptors.17 This explains the ability of either ligand to stimulate the growth of mouse or human cells.18,19 An effective strategy for blocking the action of cellular receptor tyrosine kinases is the use of soluble variants that can bind ligand and reduce its bioavailability to the cognate receptor in a highly specific manner.20,21 This has recently been demonstrated with the VEGFR1/VEGFR2-Fc decoy receptor (the vascular endothelial growth factor [VEGF]-Trap) that is currently in clinical trials as an antiangiogenic, anticancer drug.