( hybrid BCR-ABL enzyme that is always ac...)"Miracle" Cancer Drug Gleevec Can be Toxic to the Heart,Health

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 multi
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