Determining Which Patients Will Experience Chemotherapy-Induced Heart Damage

Approximately 8% of cancer patients treated with doxorubicin will experience heart damage, but a new technique might be able to help discern which patients are susceptible to heart damage, a recent study found.

Doxorubicin-induced heart damage is caused by the death of the cells located in the organ’s muscle tissue.

In the past, researchers relied heavily on animal models to investigate the phenomenon because heart muscle tissue is difficult to obtain from living patients. However, a new study published online in Nature Medicine used heart muscle cells made from the skin cells of breast cancer patients.

“In the past, we've tried to model this doxorubicin toxicity in mice by exposing them to the drug and then removing the heart for study,” said senior study author Joseph Wu, MD, PhD. “Now we can continue our studies in human cells with iPS (induced pluripotent stem cells)-derived heart muscle cells from real patients. One day we may even be able to predict who is likely to get into trouble.”

The research relied on iPS cells taken from patient skin cells, allowing access to a variety of human cell types such as brain and heart muscle cells that are difficult to obtain for studies.

During the study, researchers collected skin cells from 12 women, 8 of whom were treated for breast cancer at Stanford. Four of the Stanford patients had heart damage in response to the drug, while the other 4 did not. The remaining 4 out of 12 women served as the health control group.

“We found that cells from the patients who had experienced doxorubicin toxicity responded more negatively to the presence of the drug,” said lead study author Paul Burridge, PhD. “They beat more irregularly in response to increased levels of doxorubicin, and we saw a significant increase in cell death after 72 hours of exposure to the drug when we compared those cells to cells from healthy controls or patients who didn't have heart damage.”

Researchers speculate that the sensitivity of heart muscle cells to the drug may be caused by the increase in mitochondria compared with other cells in the body.

Although mitochondria serve as the cell power house by providing energy, they can also produce small amounts of reactive oxygen species. These molecules are a byproduct of the energy producing process and can damage cell membranes and DNA.

In the study, the doxorubicin-sensitive cells saw higher levels of DNA damage and reactive oxygen species in the presence of the chemotherapy drug.

Researchers also found that these cells were significantly more likely than the control group, or those without heart damage, to initiate a program of cellular suicide by damaging the mitochondrial membrane.

“We had assumed, based on our hypothesis, that the doxorubicin-sensitive cells would experience a more severe loss in mitochondrial capacity and that was true,” Burridge said. “But we also observed that cells made from patients who had experienced damage appeared to have slightly different baseline mitochondrial function even before the drug was applied.”

Researchers suggest that heart muscle cells could be fundamentally different in these patients compared with others because of genetic variation and could cause a negative drug response from a patient’s heart muscle cells.

In the future, researchers hope to learn the cause of the sensitivity by combining their studies of iPS-derived cells with existing genome-wide association studies, and attempt to pinpoint DNA mutations that could affect heart function.

“Doxorubicin and other similar drugs are used to treat many types of cancers, including lymphomas and leukemias,” said study co-author Melinda Telli, MD. “But we don't want to cure any of these patients of their cancers only to leave them with another life-threatening problem.”