Originally created 09/17/99

New protein attacks cancer's blood supply



WASHINGTON -- Researchers have found that a protein that helps regulate blood clotting can be changed into a cancer fighter that starves tumors.

The discovery adds to a growing list of proteins known to block cancer by preventing blood vessel formation.

Researchers led by Judah Folkman and Michael S. O'Reilly at Boston's Children's Hospital and Harvard Medical School found that antithrombin, a protein that controls the formation of blood clots, changes in molecular shape to become a cancer fighter. The transformation occurs when it is cut by an enzyme that, ironically, can originate from cancer tumors.

The reshaped molecule works by blocking formation of blood vessels that would supply oxygen and nutrients to cancer cells. The action is similar to two other proteins, endostatin and angiostatin, that the Folkman-O'Reilly team found last year. Human trials of those proteins are to start soon.

The study of the new protein appears Friday in the journal Science.

O'Reilly said he found the anticancer properties of the reshaped antithrombin molecule while studying a curious thing about small cell lung cancer.

When patients with this cancer are treated with radiation, the primary tumor is suppressed, but very often the patient then develops cancer at another site, said O'Reilly. The new cancer developed only when the first cancer was in retreat.

"It seemed that the big tumor was preventing formation of little ones," he said.

To test this, O'Reilly put lung cancer cells under the skin above both back hips of laboratory mice.

"Whichever tumor was the first to form became the dominant tumor," he said. The dominant tumors formed bulging masses, while on the opposite hip the cancer growth was tiny, with almost no blood vessels.

This meant, said O'Reilly, that the big tumor was secreting some protein that suppressed the other tumor.

The researchers isolated this protein from the mouse tumors and found that it was an antithrombin molecule that had been reshaped and was able to inhibit angiogenesis, which is the formation of blood vessels. They called the protein aaAT.

Further tests showed that aaAT is a powerful inhibitor of vessel formation with an action about like that of angiostatin and endostatin, said Folkman.

"The key finding here is that the body apparently has a storehouse of proteins whose only function is to turn off blood vessel formation," said Folkman. "This is a surprise."

Folkman said he expects other such proteins to be discovered.

"We don't know how many," he said. "We keep finding them."

The so-called antiangiogenic proteins work by preventing tumors from growing blood vessels that tap the blood circulation system of the patient. Without this connection, the tumor cells are starved for oxygen and nutrients. In laboratory mouse studies, these proteins cause tumors to shrivel and even disappear.

Human trials of endostatin and angiostatin are to begin this fall in Boston and the National Cancer Institute is planning to sponsor two clinical trials at other hospitals. These early studies are designed only to test the safety of the drugs. In monkey tests, the drugs have shown no toxic effects, even when given at high doses.

O'Reilly said it may take several years before aaAT is ready for human trials.