A team of scientists led by Thomas Force, M.D., James C. Wilson Professor of Medicine at Jefferson Medical College of Thomas Jefferson University, has shown in studies in both mice and in heart cells in culture that Gleevec can cause heart failure. The results of the study, prompted by 10 patients with chronic myelogenous leukemia (CML) who developed severe congestive heart failure while taking Gleevec, appear July 23, 2006, in an advanced online edition of the journal Nature Medicine.
"We found that the molecular target of the drug, the Abelson tyrosine kinase (ABL) protein, serves a maintenance function in cardiac muscle cells and is necessary for their health," Dr. Force explains. "While the cancer is treated effectively, there will be some percentage of patients who could experience significant left ventricular dysfunction and even heart failure from this."
"Gleevec is a wonderful drug and patients with these diseases need to be on it," he says. "We're trying to call attention to the fact that Gleevec and other similar drugs coming along could have significant side effects on the heart and clinicians need to be aware of this. It's a potential problem because the number of targeted agents is growing rapidly."
Gleevec is a new type of cancer drug – the first of its kind developed to fight cancer by turning off an enzyme that causes cells to become cancerous and multiply. In CML, an enzyme called ABL goes in overdrive because of a chromosomal mix-up that occurs during blood cell development. The genes ABL and BCR become fused and produce a hybrid BCR-ABL enzyme that is always active. The overactive BCR-ABL, in turn, drives the excessive proliferation of white blood cells that is the hallmark of CML.
According to Dr. Force, 10 patients taking Gleevec at the University of Texas' M.D. Anderson Cancer Center in Houston developed fairly severe heart failure, with no prior symptoms. Because physicians there took baseline measures of the patients left ventricular heart function, the team was able to determine that heart failure developed in these patients between two and 14 months after beginning Gleevec.
The research team probed the potential mechanisms behind the drug's possible toxic effects on the heart. Dr. Force explains that at the outset, the scientists couldn't tell if the toxicity was from the drug's effect on the known drug targets, or from an off-target effect or even a non-specific problem. "Sorting that out is important because then we can say, for example, if there are 10 more ABL inhibitors coming on line soon, and if the problem is really with inhibition of ABL, then these may have toxicity problems as well," he says.
The team proved that ABL was the guilty target by using viruses that coded for normal ABL and a Gleevec-resistant mutant. Gleevec inhibited the normal enzyme but not the mutant, and the mutant ABL "rescued" the heart cells from the toxic effects of Gleevec, proving that ABL is the relevant target. As a result, second-generation Gleevec drugs might also have similar toxicities in the heart.
"This finding is a big surprise and there may be a lot more of these," Dr. Force notes. "It's not a class effect like COX-2 inhibitors. The drugs are all tyrosine kinase inhibitors, but each tyrosine kinase is different. It's difficult to predict what tyrosine kinases will have protective roles in the heart and inhibition of them will be toxic."
Newer drugs tend to be 'dirtier' – that is, companies are developing drugs that hit multiple cancer cell targets at once to up the chances of effectiveness. Finding the exact target that, when inhibited, can cause problems with the heart, is critical to designing agents to counteract this effect.
In Gleevec, for example, blocking the PDGF receptor is crucial to its effect in thwarting gastrointestinal stromal tumors. Designing a drug to inhibit the PDGF receptor but not ABL, then, could still work against such tumors but not cause heart problems.
"We've learned something about the biology of the heart," Dr. Force says. "ABL is important for cardiomyocyte health. We also can learn something about how to stay away from these targets that are important and optimize the drugs."
In other studies, the researchers attempted to find the biological pathways involved in causing heart cells to die. They found that Gleevec appears to cause endoplasmic reticulum stress, which is initially a protective response by the cell, but if sustained, leads to cell death. They also found that treating mice heart cells with Gleevec led to the cells losing mitochondrial function, leading to cell death.
Jefferson, in collaboration with M.D. Anderson, the Cleveland Clinic and one or more European centers is planning to begin a registry for new tyrosine kinase inhibitors. "As these drugs come out, we can more easily collect data on larger numbers of patients as they take the drugs to get an idea of the incidence of heart problems," Dr. Force explains.
Dr. Force doesn't think it's possible to screen for potential heart problems that could be related to Gleevec. He notes that physicians involved in pre-release clinical trials of tyrosine kinase inhibitors will be aware of the potential problems and evaluate heart function if symptoms or signs possibly due to heart failure appear.
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