Cancer-Shrinking Drugs May Help Curtail Heart Problems

By Richard Saltus, The Boston Globe

Angiogenesis inhibitors -- drugs hailed as opening a new era in cancer treatment -- can also dramatically slow the growth of artery-blocking deposits that cause heart attacks and strokes, Boston scientists are reporting.

The results are the first evidence that the buildup of these plaques in vital coronary arteries and other vessels can be controlled by shutting off blood supply to the deposits.

The findings, so far limited to mice fed high-cholesterol diets, suggest that the angiogenesis-inhibiting drugs could become novel weapons not only in cancer but also heart disease: they are the two leading causes of death.

One of the drugs in the new study is endostatin, the glamor compound whose ability to shrink tumors in mice has focused world attention on its initial human tests expected later this year.

The inhibitor drugs work by curbing angiogenesis, the development of new, small blood vessels branching off larger, established arteries.

Angiogenesis is a normal and necessary process in wound healing and some other body functions. But the process is hijacked by malignant tumors, which recruit the tiny new vessels to nourish them so that the tumors can grow and spread.

And, the new report confirms, the fatty and fibrous plaque deposits that dangerously narrow arteries in the process called atherosclerosis also rely on angiogenesis to grow past a certain size.

The study by Dr. Karen Moulton, a cardiologist and researcher in the laboratory of Dr. Judah Folkman at Children's Hospital in Boston, is being published in the journal Circulation. Folkman is a pioneer in research on angiogenesis and its regulation by various natural and synthetic compounds.

Moulton said in an interview that further research will show whether giving angiogenesis inhibitors to people at high risk for heart disease can prevent large artery-clogging deposits from forming. It may also be, she said, that the drugs could even shrink large plaques. Also of potential benefit, said Moulton, is that cutting off the plaques' blood supply could reduce the chances that they will rupture, spilling out their contents and triggering a heart attack or stroke.

These prospects were termed ``appealing'' by Dr. Jeffrey Isner, a cardiologist at St. Elizabeth's Hosital in Boston, who wrote an accompanying editorial. But he emphasized that ``the complexity of these proposals should not be underestimated.''

Angiogenesis drugs with the opposite effect -- to promote, not block, new blood vessel growth -- are already in human tests for treating heart disease. These compounds, among them the substance known as vascular endothelial growth factor, or VEGF, stimulate the growth of new vessels that route blood flow around blocked heart arteries. They may replace bypass surgery for some heart patients.

But the angiogenesis inhibiting drugs are aimed at the atherosclerotic plaques inside blood vessels. They are formed of fatty substances and connective tissue debris that begin to build up at points where the inner lining of the blood vessel has been damaged. Often, these deposits form inside the coronary arteries that feed the heart muscle.

Moulton said it has long been noticed in post-mortem examinations of humans that a network of very fine blood vessels sometimes sprouts from the blood vessel and grows into the interior of the fatty plaque.

Only in recent years was it suggested that the new blood vessels might be critical to the plaques' growth beyond a certain size, because without the new vessels there would be insufficient oxygen and other nutrients for growth.

Moulton's idea was to choke off this vascular life-support system and see if that slowed the growth of the plaques.

Her laboratory animals were mice with a genetic mutation making them prone to developing atherosclerosis, especially when eating a high-calorie diet. All of the mice were fed these diets. At 20 weeks of age, some animals were killed and the researchers measured the size of atherosclerotic plaques in the aorta, the body's largest artery.

The remaining mice were divided into three groups. One received injections of endostatin; another received TNP 470, another angiogenesis inhibitor that's being tested in human cancer patients; and the third was injected with an inactive solution. The mice received the treatments for 16 weeks.

When killed later and examined, the original untreated mice had developed atherosclerotic plaques, and 13 percent of those plaques were being fed by newly formed capillaries -- tiny blood vessels. The smaller, more recent plaques in the mice that lived the extra 16 weeks tended not to have new blood vessels, while the larger ones were more likely to show evidence of angiogenesis.

The key finding was that the plaques that formed in the mice treated with endostatin and TNP 470 were 70 to 85 percent smaller than those that grew in the untreated mice. This was evidence that the drugs, by choking off the growth of new blood vessels, kept the plaques from growing to a dangerous size.

Treatment at different times showed that the inhibitors had much less effect if given too early -- before the plaques reached substantial size and needed new blood vessels to grow further -- or too late, after the plaques were mature.

The study, she said, shows that the tiny vessels formed by angiogenesis ``affect the progression rate of the disease, and that establishes them as a target for therapy.''

Other researchers are using angiogenesis in the opposite fashion for heart disease. Isner and others have shown that giving angiogenesis-enhancing growth factors to patients with clogged coronary arteries appears to encourage the sprouting of new, small blood vessels that create bypassses so that blood can flow past the blocked areas.

The new research raises a question: Would those growth factors also speed up the enlargement of plaques inside these patients' arteries? Apparently not: Isner wrote in his editorial that no such effects has shown up in patients treated with the growth factors.

Blood vessel inhibitors like endostatin might be given at a relatively early stage of disease, just as cholesterol-lowering statins are now used to keep blood vessels healthy. The blood vessel stimulators would be reserved for relieving arteries that are already badly clogged.

		Next Update