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A second FDA-approved tyrosine kinase inhibitor shows cardiotoxicity

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 BOSTON—More than a year after an initial study associated the tyrosine kinase inhibitor imatinib (Gleevec, Novartis) with heart failure in patients with chronic myelogenous leukemia, a second study has reported similar results for another FDA-approved targeted cancer drug, sunitinib (Sutent, Pfizer). The collaborative study involved researchers at Children's Hospital Boston, Dana-Farber Cancer Institute (Boston) and Thomas Jefferson University (Philadelphia).
The team was led by Dr. Ming Hui Chen, a cardiologist at Children's who specializes in the cardiac health of cancer patients. It appeared in the Dec. 15 issue of The Lancet, accompanied by an editorial.

As a class, tyrosine kinase inhibitors target specific signaling molecules inside cancer cells that aid cancer spread. Thomas Jefferson University's Dr. Thomas Force, who led the initial imatinib study and participated with Dr. Chen's team on the latest work, became involved when a colleague at Houston's M.D. Anderson Cancer Center told him of several cases of cardiac toxicity that resulted from his efforts to inhibit the Abl and JNK genes.
As part of Dr. Chen's team, Force examined heart-muscle cells from mice who had received the equivalent of a human dosage of sunitinib alone, where he found direct evidence of cardiotoxicity.
"It is becoming apparent that some tyrosine kinase inhibitors are too broadly targeted and interact with other ATP pockets. The multi-targeting approach is of some concern," he says, "because of possible adverse affects on the heart or other organs."

Why weren't these affects, which include heart failure, myocardial infarction and hypertension, discovered before FDA approval? Chen notes that preclinical work varies, and that with thousands of tyrosine kinases and hundreds of potential inhibitors, "one would have to look at each drug and what it targets." Of the eight related drugs that have been approved, Force adds, "only two were looked at for left ventricular (LV) function."

"One thing in drug discovery that varies," Chen notes, "is the degree of interdisciplinary collaboration. In our case, we have a close and creative collaboration between Dr. George Demitri's oncology group [at Dana-Farber] and ours in cardiology. This helped us makes the observations that we did. Dr. Demitri also points out that as we target more pathways we can inform one another's fields and identify side effects early by working together across traditional disciplinary boundaries.

"Early identification of cardiac side effects is an important part of keeping patients on life-saving cancer therapy over the long-term," Chen continues. "In this study, the cardiac dysfunction and hypertension were usually medically manageable. Most patients were able to resume therapy following temporary withholding of drug, addition of cardiac medications and/or dose adjustment.
"We are hopeful," Chen concludes, "that this type of multidisciplinary approach, from the patient's bedside to the basic cell biology laboratory, will lead to further pharmaceutical advances that will make these 'smart' cancer drugs even smarter."
Pfizer and Novartis were contacted for comment on the studies but neither responded by press time.

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