EgF Receptor Mabs and Chemotherapy/Characterization of Synergistic Interactions Between Cytotoxic Agents and Inhibitors of the Tyrosine Kinase Growth Factor Receptor Signalling Cascade

摘要

Human epidermal growth factor receptor (EGFR, HER1) and HER2 are transmembrane receptors possessing intrinsic tyrosine kinase activity. Preclinical and more recently, clinical demonstration of synergism between antibodies directed at these receptors and chemotherapeutic agents has focused our present efforts on the characterization of synergistic interactions between cytotoxic drugs and inhibitors of the tyrosine kinase growth factor signalling cascade. While we have encountered obstacles, both clinical toxicity as well as operational difficulties, in the investigation of the chimeric monoclonal antibody C225 (directed at EGFR) + paclitaxel, as summarized within this report, we have subsequently proceeded rapidly and successfully with clinical evaluation of weekly trastuzumab (HER2-directed) + weekly paclitaxel. The present report describes our most recent efforts to molecularly characterize this synergy, to perform preclinical evaluation of antitubulin agents (taxanes, vincas, and epothilones) alone and in combination with famesyl protein transferase inhibitors in mammary carcinoma cells, and to better define molecular predictors of response to inhibitors of mitogenic signal transduction, taxanes, and combinations of these agents.