Cardiotoxicity of the cancer therapeutic agent imatinib mesylate.

Center for Translational Medicine, Jefferson Medical College, 1025 Walnut Street, Philadelphia, Pennsylvania 19107, USA.
Nature Medicine (Impact Factor: 28.05). 09/2006; 12(8):908-16. DOI: 10.1038/nm1446
Source: PubMed

ABSTRACT Imatinib mesylate (Gleevec) is a small-molecule inhibitor of the fusion protein Bcr-Abl, the causal agent in chronic myelogenous leukemia. Here we report ten individuals who developed severe congestive heart failure while on imatinib and we show that imatinib-treated mice develop left ventricular contractile dysfunction. Transmission electron micrographs from humans and mice treated with imatinib show mitochondrial abnormalities and accumulation of membrane whorls in both vacuoles and the sarco- (endo-) plasmic reticulum, findings suggestive of a toxic myopathy. With imatinib treatment, cardiomyocytes in culture show activation of the endoplasmic reticulum (ER) stress response, collapse of the mitochondrial membrane potential, release of cytochrome c into the cytosol, reduction in cellular ATP content and cell death. Retroviral gene transfer of an imatinib-resistant mutant of c-Abl, alleviation of ER stress or inhibition of Jun amino-terminal kinases, which are activated as a consequence of ER stress, largely rescues cardiomyocytes from imatinib-induced death. Thus, cardiotoxicity is an unanticipated side effect of inhibition of c-Abl by imatinib.

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    ABSTRACT: Imatinib, a tyrosine kinase inhibitor which resulted in much improvement in the treatment of chronic myelogenous leukemia (CML), may adversely affect thyroid gland function. To date, assessment of thyroid function during imatinib therapy has limited to retrospective studies. The aim of this study was to evaluate the effects of imatinib on thyroid function in a prospective manner. In this prospective study, 16 newly diagnosed adult subjects with positive Philadelphia chromosome in chronic phase of CML without any other apparent underlying diseases were enrolled. Free T3, Free T4, TSH, Anti TPO and Anti thyroglobulin antibodies were measured before and after 4 and 12 weeks of treatment. Of the 16 patients, 9 were male (57.1%) and 7(42.9%) were female with a mean age of 29±5 years. There were statistically significant changes within reference ranges in serum concentrations of TSH (P=0.753 and 0.002), Free T3 (P=0.012 and 0.007) and Anti Thyroglobulin (P=0.221 and 0.041) 1 month before and 3 months after imatinib initiation, respectively. At the same time, there were no significant changes in serum Free T4 (P=0.196 and 0.650) and Anti TPO (P=0.807 and 0.600) concentrations. This study showed some significant changes on thyroid function tests during imatinib therapy. However, all of them were within the normal range without any clinical abnormalities in the course of treatment. We recommend other studies with larger sample size and longer duration of follow-up.

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