By William J. Cromie

Gazette Staff

A drug that quickly shrinks cancer tumors into harmless dormancy is being successfully tested by Medical School scientists working at Children's Hospital.

It is the second drug found by these researchers that attacks tumors by blocking the growth of blood vessels that nourish them, an idea once ridiculed as useless.

The growth blockers turn out to be natural proteins present in humans and animals, so they do not produce toxic side-effects and drug resistance, which plague virtually all other cancer drugs. Injected into mice with lung cancer, the growth inhibitors shrink huge tumors without the equivalent hair and weight loss, nausea, and diarrhea of chemotherapy.

"I've been waiting all my life for this kind of experiment," said Judah Folkman, Andrus Professor of Pediatric Surgery, referring to the new drug. "It shows that tumor growth depends on blood supplies carried in by new blood-vessel growth. Now, we've found a protein that occurs naturally in the body that blocks this growth and is one of the most powerful anti-cancer drugs in existence."

Called endostatin, the drug was discovered by Michael O'Reilly, now a clinical fellow at Dana-Farber Cancer Institute. This makes a second cancer home-run for O'Reilly, who found another such drug, called angiostatin, in 1994. Endostatin is more potent than angiostatin, and unpublished data indicates that the two work better together than when given individually.

"If it works in humans the way it works in mice, and that's a big 'if,' it could change the way we treat lung, breast, prostate, and other solid tumors," Folkman says.

A similar drug, TNP-470, discovered by Donald Ingber, an associate professor of pathology at Children's Hospital, is being tested on patients with breast and other cancers in 22 medical centers around the country.

Since 1989, Folkman has been using a much less potent inhibitor of blood-vessel growth in infants with a problem called hemangioma. In these cases, uncontrolled growth of blood vessels can be lethal.

"The inhibitor, called interferon alpha, is very slow, sometimes taking months to work, but when it kicks in, babies' lives are saved," Folkman says. "It has lowered the death rate from hemangiomas significantly at Children's Hospital."

Even arthritis might be treated by these compounds, known officially as angiogenesis inhibitors, or antiangiogenesis drugs. Inflamed cells in knee, finger, and other joints lead to growth of new blood vessels, which in turn promote the growth of more cells. The process gradually eats up protective cartilage, causing the terrible pain of uncushioned bones rubbing against each other.

Unwanted growth of blood vessels also causes blindness in some diabetics and elderly people. Robert D'Amato, assistant professor of ophthalmology at Children's, has used the angiogenesis inhibitor, thalidomide, to arrest this unwanted growth in the eyes of animals. Used as a sedative for pregnant women in the 1950s, thalidomide became infamous when it prevented the growth of arms and legs of fetuses carried by these women.

Successful Experiments

In 1991, O'Reilly began experiments to prove or disprove Folkman's hunch that large tumors produce chemicals that prevent as well as promote blood vessels from growing. The former cuts off the blood supply to smaller tumors that compete for a share of the body's limited resources. That's why some patients experience an explosive growth of smaller tumors after the primary one is removed.

After four years of work, O'Reilly found that lung tumors in mice produced angiostatin, which turned out to be the most potent suppresser of blood-vessel growth known to date. He grew large human colon, breast, and prostate tumors in mice, then treated them with the angiostatin. To the delight and surprise of everyone, the tumors shrunk to a size difficult to detect.

"We then wanted to find out if other tumors made angiostatin or a different protein or proteins," Folkman recalls. "I suggested that we examine mouse tumors called hemangioendotheliomas, which grow from cancer cells in the lining of blood vessels."

About eight months later, O'Reilly and Yuen Wan Shang, associate professor of surgery, had isolated an angiogenesis blocker and sent it to William Lane at the FAS Department of Chemistry for identification. Lane found that the protein was identical to one that makes up a piece of a larger protein called collagen XVIII, which always occurs in or surrounding blood vessels.

O'Reilly enlisted the help of research fellow Thomas Boehm to make large quantities of the smaller angiogenesis blocker, later named "endostatin." When injected into mice with massive lung tumors, endostatin does an even better job than angiostatin of reducing tumors to a size at which they no longer can grow. Preliminary results of experiments that combine endostatin and angiostatin indicate that the combination is yet more powerful.

Mice with big tumors become lethargic and seldom move around their cages. These who receive the statin drugs, however, are feisty and run away from their daily injections, "I've got the bite marks to prove it," O'Reilly remarks.

Improved Treatment

A third angiogenesis inhibitor already has been found, raising the possibility of potent drug "cocktails" tailored to shrink different kinds of tumors into indolence.

Folkman doesn't think the inhibitors will replace chemotherapy, but they may improve its effectiveness to the point where smaller amounts of these notoriously toxic drugs need to be given. Fewer drugs mean less hair loss, nausea, and weight loss.

"Tumor cells have a high rate of mutation," Folkman points out. "Eventually, the mutations result in new varieties of cells with resistance to drugs used in chemotherapy. We hope that angiogenesis inhibitors can take over when chemotherapy has to stop."

That's a perfectly reasonable expectation. The inhibitors occur naturally in blood vessels, therefore the body doesn't mount an immune resistance to them. People may be able to take them for long periods -- a lifetime if necessary -- to keep their tumors in check.

Folkman is intrigued with the idea that both endostatin and angiostatin are parts of larger proteins. Collagen XVIII, he thinks, may play a role in maintaining normal blood vessels. When vessel growth gets out of hand, endostatin may suppress it. Angiostatin sits inside plasminogen, a bigger protein involved in clotting. Prolactin, a protein that fosters milk production, carries a smaller protein that inhibits blood vessel growth.

"We may be on the verge of finding a new pattern in which many proteins have a double function," Folkman speculates. "That would be a very efficient way for nature to get things done, like a mail carrier who also delivers groceries."

Studying such systems could provide insight into the ways many vital functions of life are controlled. Folkman imagines such double messengers starting wound healing, then stopping it when healing is complete, and switching menstruation on and off.

Such a possibility could be "very exciting and rewarding," Folkman thinks. It's a hunch that scientists probably will take seriously. In 1971, when he proposed that tumor growth depends on the close presence of blood vessels, many medical experts laughed. They're not laughing any more.