miércoles, 14 de noviembre de 2012

Possible Cause of Doxorubicin-Induced Heart Damage Identified ► NCI Cancer Bulletin for November 13, 2012 - National Cancer Institute

NCI Cancer Bulletin for November 13, 2012 - National Cancer Institute

Possible Cause of Doxorubicin-Induced Heart Damage Identified

The damage to heart tissue (cardiotoxicity) sometimes seen with the drug doxorubicin may be caused by the chemotherapy’s effects on an enzyme called topoisomerase-IIβ (Top2β). This finding, from experiments in mice led by Dr. Sui Zhang of the University of Texas MD Anderson Cancer Center, was published October 28 in Nature Medicine.

The results suggest that Top2β is “an essential driver of doxorubicin-induced cardiotoxicity,” the authors concluded. This knowledge could lead to the development of drugs that are less cardiotoxic than doxorubicin, as well as to tests that identify patients who are most at risk for heart damage associated with this drug, they said.

Doxorubicin’s anticancer effects are thought to be caused by its interactions with a related enzyme, called topoisomerase-IIα (Top2α). This enzyme is expressed in rapidly dividing cells, including cancer cells, but not in mature, nondividing cells. Top2β, on the other hand, is found in all cells, and the highest levels are found in mature cells.

Because doxorubicin also interacts with Top2β, the researchers proposed that the drug might damage mature heart muscle cells through its effects on this enzyme. For their experiments, the researchers genetically engineered mice to have heart muscle cells that did not express Top2β.

When normal mice were exposed to doxorubicin, the researchers found changes in the gene expression of heart-muscle cells that were not found when mice with Top2β-deficient hearts were treated with the drug. Many of the changes occurred in cellular signaling pathways that regulate cell death (apoptosis) and the functioning of mitochondria, structures inside cells that produce most of the energy cells use.

When researchers measured the level of apoptosis in heart muscle cells to assess doxorubicin-induced damage to the heart, Top2β-deficient hearts had 70 percent fewer dying heart muscle cells than normal hearts after doxorubicin treatment. Moreover, mice with Top2β-deficient hearts had no decrease in heart function after 5 weeks of doxorubicin, whereas heart function in normal mice fell by 10 percent.

Drugs that specifically target Top2α and not Top2β “should be less cardiotoxic and, hence, more useful clinically,” they continued. And measuring Top2β expression could identify patients more likely to experience heart damage from doxorubicin. “These predictions can be tested in animals and humans,” they concluded.
This study was funded in part by the National Institutes of Health (CA102463).

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