Chronic Myeloid Leukemia – Resistance to Imatinib Mesylate (Glivec®)


Authors: J. Naušová;  M. Priwitzerová;  M. Jarošová 1;  K. Indrák 1;  E. Faber 1;  V. Divoký
Authors‘ workplace: Ústav biologie LF UP, Olomouc ;  Hemato-onkologická klinika LF UP a FN, Olomouc 1
Published in: Čas. Lék. čes. 2006; 145: 377-382
Category: Review Article

Overview

Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by an abnormal fusion gene BCRABL. BCR-ABL encodes a constitutively active Bcr-Abl tyrosine kinase, which is required and sufficient for cellular transformation. Bcr-Abl is, therefore, an ideal target for pharmacotherapy. Imatinib Mesylate (Glivec®) is a specific inhibitor of Bcr-Abl kinase. Imatinib shows high efficiency and low toxicity in treatment of CML patients. The main problem of imatinib treatment is the development of resistance. The mechanisms of resistance can be divided into two groups. The first group is characterized by reactivation of Bcr-Abl kinase in spite of continual imatinib presence. This can be caused by BCR-ABL amplification, overexpression or mutation in Abl kinase domain. Imatinib might not even reach the target Bcr-Abl protein (possible causes: drug efflux or imatinib binding to alpha1-acid glycoprotein). In the second group of resistance mechanisms, the Bcr-Abl kinase is inhibited but the resistance is maintained by other signal transducers (e.g. Src kinases). Standard cytogenetics as well as assay evaluating the phosphorylation status of Bcr-Abl substrate and/or sequencing of Abl kinase transcript can be used to test the mechanism of resistance. Treatment of patients can be re-evaluated on the basis of the status of IM resistance. 

Key words:
chronic myeloid leukemia, BCR-ABL, imatinib, resistance.


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