Chronic myeloid leukaemia is associated with a specific translocation between chromosomes 9 and 22 that results in the formation of a chimaeric gene. This gene, when transcribed, produces the BCR-Abl oncoprotein which hastyrosine kinase activity and the ability to prevent apoptosis, but has no effect on cellular proliferation. Imatinib mesylate, an inhibitor of the BCR-Abl transcript modelled on the ATP binding pocket of the Abl oncoprotein, prevents phosphorylation of effector molecules and induces apoptosis. Imatinib has limited effectiveness when BCR-Abl cells are in the quiescent cell-cycle state of G0. A life-long regimen of imatinib should reduce the risk of relapse from cells leaving Go. Up-regulation of BCR-Abl expression, ATP binding pocket mutations, up-regulation of MDR1 and over-expression of Pgp are all thought to limit the effectiveness of imatinib. Advanced BCR-Abl positivity is associated with complex mutations, which are thought to have a cumulative effect on the BCR-Abl oncoprotein in disrupting normal signal transduction, making these cells refractory to monotherapy alone. Combination therapy is thought to overcome this. Research studies have identified imatinib as a potential treatment option for a diverse range of malignancies associated with BCR-Abl, platelet-derived growth factor receptor (PDGFr) and c-Kit pathways. This may extend the application of this special therapy in the future.
|Number of pages
|British Journal of Biomedical Science
|Published - 2004