Sti‐571 in Chronic Myelogenous Leukaemia

STI-571 (imatinib mesylate) is the prototype for signal transduction inhibitors. It is the model for rational drug design, in that it targets the genetic mutation of the disease. STI-571, a 2-phenylaminopyrimidine, is a highly selective inhibitor of the protein tyrosine kinase family, which includes BCR–ABL protein, the platelet-derived growth factor (PDGF) receptor and the c-kit receptor. Chronic myelogenous leukaemia (CML) is a stem cell disorder characterized by the Philadelphia chromosome and is dependent on the constitutively active tyrosine kinase protein BCR–ABL. In the CML model, STI-571 competitively binds to the ATP-binding site of the BCR–ABL and inhibits protein tyrosine phosphorylation. This review begins with a historical overview of CML therapy, then discusses STI-571 and its impact in the treatment of CML via clinical trials. The second part of this review addresses the issue of CML resistance to STI-571. A summary of the currently known mechanisms of resistance and the available options to overcome resistant disease is reviewed.

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