HOUSTON - Doxorubicin, a 50-year-old chemotherapy drug still in widespread use against a variety of cancers, has long been known to destroy heart tissue, as well as tumors, in some patients.
Scientists have identified an unexpected mechanism via the enzyme Top2b that drives the drug's attack on heart muscle, providing a new approach for identifying patients who can safely tolerate doxorubicin and for developing new drugs. A team led by scientists at The University of Texas MD Anderson Cancer Center reports its findings about the general DNA-damaging drug today in the journal Nature Medicine.
"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 Edward T.H. Yeh, M.D., professor and chair of MD Anderson's Department of Cardiology and senior author of the study.
"However, its use is limited by its cardiotoxicity, which can lead to heart failure," Yeh said. "We're excited because we've identified the molecular basis for doxorubicin's damage to the heart."
A tale of two enzymes
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, virtually absent in cancer cells but present in normal cells.
Doxorubicin destroys cancer cells by binding to Top2a and to DNA, causing irreparable damage in the form of double-strand DNA breaks. This triggers apoptosis, a cellular suicide mechanism designed to prevent the growth of defective cells.
Yeh and colleagues found that the drug binds to Top2b in cardiomyocytes - heart muscle cells - but it inflicts its damage in a different manner from its attack o
|Contact: Scott Merville|
University of Texas M. D. Anderson Cancer Center