Mechanisms of resistance to imatinib (STI571) and prospects for combination with conventional chemotherapeutic agents.

Imatinib (STI571, Glivec) is a small molecule drug selected for its ability to inhibit the Bcr-Abl kinase, the pathogenic molecular abnormality in chronic myelogenous leukemia (CML). It also is an efficient inhibitor of the Kit and platelet-derived growth factor receptor tyrosine kinases. In vitro studies have demonstrated that this drug potently inhibits proliferation and induces apoptosis of cells that depend on activation of these kinases. Phase I clinical studies have demonstrated remarkable activity against CML. However, these studies, as well as a variety of experimental models, have suggested that clinical resistance to STI571 could develop. The mechanisms for the development of this resistance will be discussed along with the potential for circumventing STI571 resistance by combining it with traditional anti-neoplastic agents.