A cancer drug hailed for its ability to rescue those dying from leukaemia could end up giving them heart failure, a study suggests. Doctors say that the side effects of cancer drugs are demanding more attention now that more and more patients are saved from the initial disease.
Imatinib mesylate, marketed under the name Gleevec, was hailed as a revolutionary drug when introduced in the United States in 2001. It was carefully designed to target the mutated protein in a form of deadly leukaemia, and has a huge impact on the survival rates of people with this disease.
Now a team of researchers in the United States has shown that the cancer drug unexpectedly kills heart muscle cells and seems to promote heart failure in some patients. They report their results in Nature Medicine1.
The researchers say that patients should continue to take the drug because it is so powerful at treating cancer, whereas the frequency of heart problems is unknown and the problem may be treatable with common heart drugs.
But the study highlights a trend in cancer medicine: as more effective drugs save more lives, patients and doctors are forced to consider side effects that could affect patient health once the immediate threat has passed, sometimes many years later.
Heart failure is a particularly serious consequence because it could be just as life-threatening as some forms of cancer, says Thomas Force at Jefferson Medical College in Philadelphia, Pennsylvania, who led the study. "You don't want to trade one lethal disease for another."
Runaway mutation
Gleevec acts on an enzyme called a tyrosine kinase that is mutated in chronic myelogenous leukaemia and fuels runaway cell division.
This enzyme was not known to be important in heart muscle cells. But Force's colleagues noticed that some patients taking Gleevec developed heart failure over only a few months, despite having had no signs of it beforehand. They studied ten such patients and found that their hearts had lost much of their ability to pump blood, and that their heart muscle cells appeared abnormal under the microscope.
To find out exactly what was going on, the researchers treated mice with typical doses of Gleevec and found that it also caused their hearts to weaken after several weeks. By blocking the tyrosine kinase, the drug seems to stress the protein-processing machinery of heart cells and eventually causes cell death.
Two other cancer drugs, which block related tyrosine-kinase enzymes, have also been shown to promote heart failure in some people. One is trastuzumab (Herceptin), used to treat breast cancer; the other is sunitinib malate (Sutent) for kidney and stomach cancers. "It looks like they are causing all kinds of havoc with the heart," says cardiologist Douglas Mann at Baylor College of Medicine in Houston, Texas. Certain drugs used for chemotherapy are also known to cause heart damage.
Clinical trials
Novartis has issued a statement acknowledging that the results are interesting, but adding that the data is so far limited, and more work needs to be done. "Novartis is committed to patient safety and monitors all reports of adverse events including any affecting the heart," the statement says.
"Results from clinical trials and postmarketing safety data, involving more than 200,000 patient years of clinical treatment, have shown that the incidence of heart failures among patients taking Gleevec is extremely rare. The observations of this preclinical study do not change the positive benefit/risk ratio of Gleevec."
Pharmaceutical companies developing new tyrosine-kinase inhibitors against cancer, of which there are many in development, should carefully monitor their patients for cardiac effects, as should the doctors and patients themselves, Mann says. These molecules work all over the body, and interfering with them could also have other, unforeseen side effects.
But the benefit certainly seems to outweigh the problems, Mann adds. "Yes, we should use these drugs. No, we shouldn't use them without proper monitoring," he says
References
Kerkala R., et al. Nature Medicine , AOP doi: 10.1038/nm1446 (2006).
据美联社报道，一种可对白血病起到良好治疗效果的抗癌药物可能会对心脏造成破坏，不过，研究人员称，那些需要格列卫的白血病病人不应当放弃使用这种药物。
托马斯-杰弗逊大学杰弗逊医学院医学授课教师弗尔斯医生称，尽管可以对白血病起到良好的治疗效果，格列卫可能会使一些病人心力衰竭。《自然医学》杂志电子版23日刊登了他的研究报告。弗尔斯是根据有10名服用格列卫的慢性粒细胞性白血病病人出现了严重的郁血性心脏衰竭症状后开始这项研究工作的。这十名出现心脏衰竭症状的病人是在德州大学安德森癌症中心服用格列卫的。他们在服用格列卫之间并没有心脏疾病症状，这些症状是在服药两个月至十一个月后出现的。
药品的制造者诺华药品公司称，格列卫今年头六个月的全球销售额为12亿美元。弗尔斯在接受电话采访时称：“格列卫是一种效果出色的药，那些患有白血病的病人应当继续服用它。它肯定是一种救命药。它不会因为对心脏产生副作用而退出市场。”
弗尔斯称，他试图让人们注意到格列卫和其它类似药品可能会对心脏产生重大副作用，医生们应当对此加以注意，关注相关症状。那些出现症状的病人可以接受心脏治疗。
诺华公司称，这项研究的数据有限，需要对此进行更多的研究以便更好的了解这类研究和它们对病人看护潜在影响的关系。公司在一份书面声明中称，药品的处方信息中包括了有关心脏问题的数据。公司称，临床实验和上市后的安全性数据显示，服用药物病人出现心力衰竭症状的例子非常罕见。弗尔斯的工作没有改变“格列卫积极的益处/风险比例。数千名患癌症和其它威胁生命疾病的病人正在服用格列卫。”
编辑：杉杉
