Discovery and Development of Iressa: The First in a New Class of Drugs Targeted at the Epidermal Growth Factor Receptor Tyrosine Kinase

摘要: The epidermal growth factor receptor (EGFR) is a promising target for anti-cancer therapy because of its role in tumour growth, metastasis and angiogenesis, resistance to chemotherapy radiotherapy. This chapter describes low-molecular- weight EGFR tyrosine kinase inhibitor (EGFR-TKI), Iressa (gefitinib, ZD1839). potent EGFR-TKI which blocks EGF-stimulated autophosphorylation cells selectively inhibits cell growth. In studies with mice bearing range human tumour-derived xenografts, given orally, once daily, inhibited dose-dependent manner. Long-term (>3 months) treatment xenograft-bearing was well tolerated, completely the xenografts derived from A431 highly express EGFR, induced regression advanced A431-derived tumours. No Iressa-resistant tumours appeared during treatment, but some regrew following drug withdrawal. level expression did not determine xenograft sensitivity Iressa. These preclinical indicated potential utility wide tumours, established that continuous once-daily oral dosing might be suitable therapeutic regimen. first clinical confirmed an oral, once-daily, regimen generally tolerated shows activity cancer patients. Phase II trials, patients non-small-cell lung (NSCLC) who had been previously treated chemotherapy, demonstrated at daily dose 250 or 500 mg has favourable safety profile activity. lower (250 mg/day) better as effective mg/day dose. these phase studies, predict response treatment. III addition standard two-drug regimens, untreated NSCLC patients, failed improve disease-free overall survival. Studies are now underway investigate how can used alternative sequence NSCLC, explore efficacy other including head neck, breast colorectal.