Certain cancer drugs damage the heart and may cause death

Hedgehog antagonists, a set of promising new anticancer agents, may be deadly for people with heart disease, a new study suggests.

MONDAY JUNE 23, 2008 (foodconsumer.org) -- Hedgehog antagonists, a set of promising new anticancer agents, may be deadly for people with heart disease, a new study suggests.

The study showed that mice with heart disease treated with hedgehog antagonists experienced further deterioration of cardiac function and ultimately death.

The study was conducted by David Ornitz, M.D., Ph.D., at Washington University School of Medicine in St. Louis and colleagues, and published June 20, 2008 in the advance online publication of the Journal of Clinical Investigation.

Ornitz and colleagues found that the drugs interfered with a biochemical process that promotes growth in some cancer cells. But as a side effect, the drugs blocked hedgehog signaling in the heart of adult mice and caused many small coronary blood vessels to disappear.

"This finding should serve as a warning that these drugs might have adverse effects on the heart and that it could be very important to monitor patients' cardiovascular health when using this type of anticancer drug," said Ornitz.

Hedgehog antagonists inhibit the hedgehog signaling pathway, a chain of biochemical signals that regulate cellular growth and differentiation. Abnormal activation of the hedgehog pathway is implicated in many different types of cancer.

The researchers have recently found the hedgehog signaling pathway to be vital to the development of the heart's blood supply. The process is important not only in the early development of the heart, but also in adult hearts to maintain cardiac blood vessels.

They discovered a complete blockage of hedgehog signaling in the hearts of adult mice, causing many small coronary blood vessels to disappear.  The heart muscle was thus short of oxygen, which lead to heart failure. 

In mice with experimentally induced heart attacks, even mildly inhibited hedgehog signaling led to a worsening of their heart conditions.

"We gave mice small amounts of antibodies against hedgehog, and in those that had a recent myocardial infarction (heart attack), this led to poorer heart function and some lethality," explained coauthor Kory Lavine, M.D., Ph.D., now a resident in the Cardiovascular Division of the Department of Medicine at Washington University School of Medicine. 

"We've shown that small decreases in the hedgehog pathway in the setting of heart disease can lead to deleterious outcomes, and since a number of patients with cancer also have heart disease, this raises concern for those who might be treated with hedgehog antagonists."

Hedgehog antagonists are being studied for their efficacy in treating several cancers, including basal cell carcinoma (a type of skin cancer), prostate cancer, pancreatic cancer, colorectal cancer, and medulloblastoma (a type of brain tumor).

The current study was the first to demonstrate that inhibiting hedgehog signaling, which is essential to maintain a healthy supply of blood vessels in heart muscle in adult organisms, may help fight cancer, but may backfire to hurt the heart in patients with heart disease.

"Nobody had ever looked for hedgehog signaling in the adult heart before," said Ornitz. 

"Kory discovered that the hedgehog signaling pathway is a mechanism to regulate the heart's vasculature by influencing growth factors that promote blood vessel growth. The body can tune the hedgehog pathway to modulate its signal and increase and decrease blood vessels on demand, providing a mechanism to ensure a constant supply of oxygenated blood for the energy-hungry cells of heart muscle."


By Sue Mueller, and edited by Heather Kelley.
Jun 23, 2008 - 5:44:44 PM