Epidermal growth factor receptor tyrosine kinase inhibitors as anticancer agents

The epidermal growth factor receptor (EGFR)-driven autocrine growth pathway has been implicated in the development and progression of the majority of the most common human epithelial cancers, making the blockade of this growt h pathway a promising anticancer therapeutic strategy. Different approaches have been developed to block EGFR activation and/or function in cancer cel ls. In the past 15 years, various anti-EGFR blocking monoclonal antibodies (MAb), recombinant proteins containing transforming growth factor-alpha (TG F alpha) or EGF fused to toxins, and tyrosine kinase inhibitors (TKIs) have been generated and their biological and potentially therapeutic properties characterised. One of these agents, MAb IMC-C225, a chimeric human-mouse I gG(1) MAb, is the first anti-EGFR agent to enter phase II to III clinical t rials in patients with cancer. Several small compounds that block the ligand-induced activation of the EGF R tyrosine kinase have been developed. Among these EGFR-TKIs, various quina zoline-derived agents have been synthesised and have shown promising activi ty as anticancer agents in preclinical models. ZD1839 ('Iressa'),(1,2) an a nilinoquinazoline, is an orally active, selective EGFR-TKI which is current ly under clinical evaluation in phase II to III clinical trials in patients with cancer. Preclinical data for ZD1839 strongly support the possibility of potentiating the antitumour activity of conventional chemotherapy with a gents that selectively block the EGFR.