Study Sheds Light on Gleevec-Linked Cardiotoxicity
Anti-leukemia drug is toxic to cardiac cells in mice and humans
TUESDAY, July 25 (HealthDay News) -- Imatinib mesylate (Gleevec) is highly effective in treating chronic myelogenous leukemia, but is cardiotoxic in studies of mice and cultured cells, and can lead to heart failure in humans, according to a report published online July 23 in Nature Medicine.
Clinical trials of Gleevec, an inhibitor of the Bcr-Abl oncogenic fusion protein, had indicated that treated patients without a prior history of heart disease could develop peripheral edema and dyspnea, according to Thomas Force, M.D., of Thomas Jefferson University Hospital in Philadelphia, and colleagues. To further investigate, they examined the cases of 10 individuals who developed severe congestive heart failure with no obvious cause after taking Gleevec and also treated mice with the drug.
The researchers found that the imatinib-treated mice developed left ventricular contractile dysfunction. Biopsies of cardiac tissue from patients and mice showed mitochondrial abnormalities indicative of a toxic myopathy. Imatinib was toxic to cardiomyocytes due to prolonged activation of the endoplasmic reticulum stress response, which caused the activation of prodeath cellular signaling pathways, according to the study. The authors were able to rescue cardiomyocytes from imatinib toxicity by giving them a form of the c-Abl gene that was resistant to Gleevec.
"Thus, cardiotoxicity is an unanticipated side effect of inhibition of c-Abl by imatinib," Force and colleagues conclude. They suggest that "individuals who are on imatinib should be followed closely for symptoms and/or signs of left ventricular dysfunction."