The Heart Breaking Chemotherapy Connection

Doxorubicin trial to learn more about which cancer patients vulnerable to heart damage

(RxWiki News) Chemotherapy can be heartbreaking. Literally. A drug that has been used for half a century to treat a broad array of tumors, also destroys heart tissue. Why this happens is finally becoming clear.

The chemotherapy doxorubicin – brand names Adriamycin, Rubex – activates an enzyme called Top2b which leads the drug to attack heart muscle.

This finding could lead to a way to not only identify patients who can – and cannot – safely take this medication, but also open the path for new drug development.

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Researchers at The University of Texas MD Anderson Cancer Center led a study that uncovered this mechanism.

“Even in this age of targeted therapies, doxorubicin remains an effective agent used mainly in combination with other drugs against a variety of malignancies, including breast, lung, ovarian and bladder cancers, as well as leukemia and lymphoma,” said senior study author Edward T.H. Yeh, MD, professor and chair of MD Anderson’s Department of Cardiology.

“However, its use is limited by its cardiotoxicity, which can lead to heart failure,” Dr. Yeh said. “We’re excited because we’ve identified the molecular basis for doxorubicin’s damage to the heart.”

There are two types of the enzyme that causes the toxic side effects by damaging DNA - topoisomerase2 (Top2). Top2a is seen in high levels in cancer cells, but essentially absent from normal cells.

Just the opposite is true for Top2b, which is not seen in cancer cells so much as it is in normal cells.

To kill cancer, doxorubicin latches on to the Top2a and to DNA to destroy the cancer cells. In some patients, the drug also binds to Top2b which in turn attacks healthy heart muscle cells.

Through a series of animal studies the research team learned that doxorubicin causes heart damage by damaging DNA and by interfering with the heart muscle’s metabolism. These actions depend on Top2b.

The authors wrote, “Specifically, our findings implicate Top2β as an essential driver of doxorubicin-induced cardiotoxicity.”

To learn more about how all of this happens, a clinical trial is now being conducted with cancer patients who have received doxorubicin. Two groups of patients are involved – those who have had heart problems and those who have not.

The objective of the trial is to learn if measuring levels of Top2b can indicate if they are likely to develop heart problems when taking doxorubicin. If so, a simple blood test could be used to determine who can and cannot take the medication.

Drugs may also be developed to target Top2b, according to researchers.

“We want to make sure that cancer patients will have healthy hearts to enjoy their life after successful cancer treatment,” Dr. Yeh said in a press release.

Findings regarding this medication were published October 28 in Nature Medicine.

This study is supported by the Cancer Prevention Research Institute of Texas and McNair Medical Institute, US National Institutes of Health, the New Jersey Commission on Cancer Research Grant, US Department of Defense Idea Award and Concept Award.

The authors disclosed no financial conflicts of interest.

Review Date: 
October 28, 2012