Plaque deposits in arteries are nourished by tiny blood vessels, researcher Karen Moulton has found. By giving animals drugs being tested to shrink tumors, she's been able to reduce plaque growth. Photo by Kris Snibbe.

Two drugs being tested to shrink cancer tumors are showing promise for slowing growth of fatty deposits in blood vessels that can cause heart disease and stroke.

One of the cancer drugs, TNP-470, has already passed safety tests in adults and children. When given to mice with high cholesterol, it dramatically inhibits buildup of plaque that clogs and then blocks blood flow in arteries serving the heart and brain.

The second drug, endostatin, created a media sensation, when, in 1997, researchers announced that it eliminated tumors in mice without causing harmful side effects. Experiments in the same laboratory that developed endostatin now show that it can do double duty in rodents' cardiovascular systems.

"It's clear that both drugs significantly inhibit growth of plaque in blood vessels," says Karen Moulton, an instructor in medicine at Harvard Medical School and researcher at Children's Hospital in Boston. "If the findings hold up in future studies, such agents could delay the progression of heart disease, and become part of strategies to prevent heart attack and stroke."

Testing of endostatin on humans with cancer is slated to begin later this year. TNP-470 has already arrested or halted the spread of cervical cancer and the growth of brain tumors in a few patients, and researchers are now trying to determine what dosages are best for treating various cancers. Moulton notes that more tests on animals need to be done before these and related drugs can be given to humans with heart disease.

Growing Tumors and Plaque

TNP-470 and endostatin suppress the growth of blood vessels, something that, at first, sounds detrimental. But in experiments in the early 1960s, Judah Folkman, now Andrus Professor of Pediatric Surgery at Harvard Medical School, discovered that mouse tumors do not grow beyond the size of a pinhead unless they are nourished by food and oxygen carried to them by blood vessels. Folkman has spent most of his career developing so-called angiogenesis (vessel-growth) inhibitors to deprive tumors of this nourishment.

For 100 years, cardiologists have known that tiny blood vessels, or capillaries, exist in the fatty, fibrous gunk that accumulates inside arteries. The capillaries grow out of larger vessels that supply blood to arteries and veins.

"We guessed that plaque grows faster when fed by blood vessels, just like tumors," notes Moulton. She and her colleagues, including Folkman, decided to conduct an experiment to prove this to themselves and the rest of the world.

They started with mice bred to develop arteriosclerosis, especially when fed a high cholesterol diet. Such mice are often used as models of humans who get heart disease.

The rodents were fed fatty food for 20 weeks, well into their adulthood. "We wanted to make sure we could inhibit plaque growth in a setting of markedly elevated cholesterol," Moulton remarks.

The researchers then checked 25 percent of the mice to be sure that their arteries were diseased, and divided the remainder into three groups. As they continued on the high-cholesterol diet, a third of the mice received TNP-470, a third were given endostatin, and a third got an inactive salt solution. At the end of 16 weeks of such treatment, the mice were sacrificed and their blood vessels examined.

Endostatin inhibited plaque growth 85 percent compared with those mice that received no drugs, Moulton reported this month in the journal Circulation. TNP-470 cut plaque deposits by 70 percent.

"Both agents meaningfully inhibited growth of plaque," Moulton said in an interview. "That opens up the possibility that drugs can be used to manipulate its growth and delay -- or even prevent -- the development of heart disease and stroke."

Affordable pills that people can take to reduce the buildup of blockages in their arteries, however, are not just around the medical corner. Moulton guesses that doing more tests on animals, then humans, and obtaining additional knowledge of exactly what goes on in the blood vessels, will delay the availability of such drugs 5 to 10 years.

People usually don't feel symptoms of heart disease, like chest pains, until a coronary artery becomes more than 70 percent blocked. However, sections of plaque can burst, causing a blood clot to form in the artery. Broken pieces can also be carried downstream until they eventually clog smaller vessels. Strokes are often triggered in this way.

Moulton wants to know if capillaries bleeding inside plaque make the sections of plaque more liable to burst.

"It's not always the largest deposits that burst and cause problems," Moulton says. "So we need to determine which components of plaque make it most vulnerable to rupture. Then we must find out if inhibition of blood-vessel growth with drugs will prevent plaque breakup."

To Grow or Not

While Folkman, Moulton, and others work on drugs to inhibit growth of blood vessels, some colleagues are trying to stimulate this growth. Cardiologist Michael Simons, for example, leads a group of researchers who give patients basic fibroblast growth factor (bFGF) to help them grow new blood vessels that bypass severely clogged arteries in their hearts.

Of 66 patients given injections of growth factor into their hearts, "about 80 percent show a reduction in their symptoms and an increased capacity for exercise," notes Simons, who is an associate professor of medicine at Harvard Medical School. His team works at Beth Israel Deaconess Medical Center in Boston.

Nearby at St. Elizabeth's Medical Center, cardiologist Jeffrey Isner heads a team that is having success using vascular endothelial growth factor (VEGF) for the same purpose.

When a heart artery becomes completely blocked, the body secretes these factors, which stimulate the growth of so-called collateral vessels. It's amazing to see multiple collaterals growing out of the side of the larger, blocked artery, making their way past the clot, and reconnecting on the other side of the obstruction. This natural process is not very efficient, however, so Simons, Isner, and other researchers try to improve it by providing extra supplies of growth factors.

So far, the treatment appears to be working. But won't it interfere with drugs given to inhibit blood vessel growth in patients with cancer and arteriosclerosis?

Folkman says he is often asked this question. Moulton's findings, he replies, provide evidence that cancer patients can take angiogenesis inhibitors without making any heart disease they have worse.

"Rather than being incompatible, the two types of drugs might be used at different stages of heart disease," Moulton adds. At earlier stages, angiogenesis inhibitors may reduce plaque buildup, thus delaying or preventing heart disease. Later, when arteries are almost blocked and chest pains and other problems appear, growth factors might relieve pain, fatigue, and other symptoms.

She cautions, however, that "a great deal more knowledge and experimentation is needed before we find out how these two somewhat paradoxical treatments can be applied to the same disease."