Molecular details provide new answer for heart-threatening chemotherapy
An effective drug that kills cancer by damaging DNA also attacks heart muscle, which for some patients leads to heart failure. In new research, scientists have discovered how the drug attacks the heart, opening potential new options to prevent or minimize the life-threatening side effect.
Doxorubicin is a 50-year-old chemotherapy drug still in widespread use in combinations to treat a variety of cancers, including breast, ovarian, lung and bladder cancers as well as leukemia and lymphoma.
"However, its use is limited by its cardiotoxicity. We're excited because we've identified the molecular basis for doxorubicin's damage to the heart," said Edward T.H. Yeh, M.D., professor and chair of MD Anderson's Department of Cardiology and senior author of the study reported online today at Nature Medicine.
This knowledge can mobilize researchers to find a way to identify those who are sensitive to heart damage by doxorubicin and either use other drugs, or include cardio-protective drugs and more closely monitor patients.
Another exciting alternative is to develop drugs that only target Top2a, Yeh said. "We want to make sure that cancer patients will have healthy hearts to enjoy their life after successful cancer treatment."
Two enzymes, different targets and effects
Doxorubicin binds to topoisomerase2 (Top2), an enzyme that controls the unwinding of DNA necessary for cell division. There are two types of Top2, Yeh said.Top2a is overproduced in cancer cells but largely absent in normal cells. The reverse is true for Top2b.
Doxorubicin destroys cancer cells by binding to Top2a and to DNA, causing irreparable damage in the form of double-strand DNA breaks and triggering the cell's suicide mechanism.
Yeh and colleagues found that the drug binds to Top2b in cardiomyocytes - heart muscle cells - but inflicts its main damage in a different manner from its attack on cancer cells.
Mouse experiments found that initial harm is caused by DNA damage, much like the drug inflicts cancer cells.However, in the longer term doxorubicin binds to Top2b in heart muscle cells and causes mitochondrial dysfunction and generation of harmful reactive oxygen species (ROS).Mitochondria generate a cell's energy and in the process control ROS.
"We provide an explanation for the classic observation that doxorubicin generates major ROS, but we show that the entire cardiotoxicity cascade depends on Top2b," Yeh said.
Clinical study tests biomarker potential
The team's mouse model experiments led to a clinical study now under way among two types of cancer patients - those who have received small amounts of doxorubicin and developed heart problems, and those who received large amounts of the drug yet without apparent heart damage.
The study aims to find whether patients' blood levels of Top2b indicate their sensitivity to doxorubicin-induced heart damage. It's funded by a $1.84 million, 5-year grant from the Cancer Prevention and Research Institute of Texas. If the study unfolds as hoped, a simple blood test could indicate who will be sensitive to doxorubicin.