Tyrosine kinase inhibitors in cancer therapy

Cancer is the second leading cause of death in the western world. Despite advances in diagnosis and treatment, overall survival of patients remains poor. Scientific advances in recent years have enhanced our understanding of the biology of cancer. Human protein tyrosine kinases (PTKs) play a central role in human carcinogenesis and have emerged as the promising new targets. Several approaches to inhibit tyrosine kinase have been developed. These agents have shown impressive anticancer effects in preclinical studies and are emerging as promising agents in the clinic. The remarkable success of BCR-ABL tyrosine kinase inhibitor imatinib (ST1571) in the treatment of chronic myeloid leukaemia has particularly stimulated intense research in this field. At least 30 inhibitors are in various stages of clinical development in cancer, and about 120 clinical trials are ongoing worldwide. In this review, we focus on the role of tyrosine kinases in cancer and the development of specific small molecule inhibitors for therapy. We also provide a critical analysis of the current data on tyrosine kinase inhibitors and highlight areas for future research. Issues with regards to the design of clinical trials with such agents are also discussed. Innovative approaches are needed to fully evaluate the potential of these agents, and a concerted international effort will hopefully help to integrate these inhibitors in cancer therapy in the near future. (C) 2004 The Canadian Society of Clinical Chemists. All rights reserved.