Thousands of women throughout the world are given doses of the drug Herceptin -- usually in combination with other drugs -- as a treatment for breast cancer. However, the drug has been linked to severe heart damage and even cardiac failure.

Although medical science wasn't able to explain why the drug damaged otherwise healthy hearts, the FDA approved Herceptin, fully aware of the dangers it posed for female patients.

Recently, a team of researchers has identified the probable reason the cancer drug causes cardiac failure. Its suggested "solution" to the problem? The creation of more drugs.

According to the research report, published in Nature Medicine, Herceptin targets the protein Her2 (for a protein related to human epidermal growth factor receptor), which is produced in excess in some breast cancer cells. The new study indicates that this protein may be needed for proper heart cell function.

"It was possible that Herceptin triggered cardiac malfunction by a number of mechanisms, but now it appears that the drug's direct action on erbB2 is the culprit," said Kuo-Fen Lee, a Salk associate professor and senior author of the study appearing in Nature Medicine.

To reach their conclusions, they studied the drug's effect on mice.

"This mouse model will help us identify new mechanisms to protect patients from Herceptin cardiomyopathy, and thereby allow more aggressive and early use of Herceptin for a broad range of human cancers," said co-author Ken Chien, director of the Institute of Molecular Medicine at the University of California, San Diego (UCSD) and Salk adjunct professor.

Yet, the study clearly showed that the suppression of erbB2 in mice resulted in numerous other problems.

Cardiomyocytes -- the muscle cells responsible for pumping blood through the heart -- were less elastic than normal, and therefore less effective at the contraction and relaxation needed to maintain heart beat.

In addition, the mice (whose erbB2 gene was altered so that it would be shut off in the heart after birth) were more susceptible than their normal counterparts to stress. They were less able to recover from tightening of the aorta, the heart's main artery, which results in high blood pressure.

In short, this is the damage being done to patients receiving the drug. To compound the problem, almost all women taking Herceptin also receive or have received other anti-cancer drugs, particularly anthracyclines. The researchers, therefore, looked also at the effect of this drug combination and found that the dangerous side effects were heightened.

"It appears that the loss of erbB2 function caused by Herceptin makes cardiac muscle more susceptible to anthracycline toxicity," said Lee.

Again, the researchers suggested that the solution is to be found in more drugs.

"These results suggest it may be appropriate to examine alternative chemotherapeutic agents in combination with Herceptin, in order to avoid the increased risk of heart disease associated with combined Herceptin/anthracycline therapy. If we could develop agents that can stimulate the heart, particularly cardiomyocyte contractility, then those might allow you to use Herceptin aggressively while protecting the heart," stated Lee.

Preventing the adverse side effects of Herceptin in the heart would allow more widespread use of Herceptin for treating other forms of cancer that frequently have an abundance of erbB2, such as prostate, lung and ovarian cancers, the researchers noted.

The study was funded, in part, by Genentech, Inc., the company that, along with Swiss drug maker Roche, manufactures and markets Herceptin.

According to a Reuters report in March 2002, sales of Herceptin rose 50% to $453 million in 2001 and a single course of Herceptin treatment costs approximately $18,470. The drug was recently approved in Britain, where officials say it will cost the government health service approximately $24 million to treat an estimated 2,000 women eligible for the drug.

SOURCES: "ErbB2 is Essential in the Prevention of Dilated Cardiomyopathy," Nature Medicine, April 30, 2002.