Cancer scientists newly hopeful but wary of miracles 2 drugs rid lab miceof cancerous tumors; 'Cautiously optimistic'; Testing in humans at least a year away

THE BALTIMORE SUN

Two recently developed drugs that wipe out cancer in animal experiments hold real promise, scientists say. But when it comes to curing millions of human victims, the road to a miracle may still be littered with land mines.

Crucial tests of whether these drugs work in people are still at least a year away, perhaps much longer. Disappointed by past claims of a cure, many cancer patients aren't getting their hopes up.

Scientists are just as cautious.

"I'm not aware of any compounds with more promise than these," said Stephen B. Baylin, professor of oncology at the Johns Hopkins medical school and director of research at its cancer center, noting that the drugs have inspired "unprecedented" optimism. But in the next breath, he added: "The hope is that there's some reason for that optimism."

The hurdles are many. It's difficult to produce drugs on a large scale. They could quickly break down in the human body and require huge doses. Despite encouraging results in lab animals, they could trigger toxic side effects in humans - and could harm stroke victims, children or people recovering from wounds.

Experiments prove the drugs can eliminate three types of common human cancer when transplanted into lab mice. But they might not work at all in people.

The National Cancer Institute, responding to a New York Times article Sunday that publicized the new drugs, issued a statement yesterday saying it had made testing of these drugs "a high priority." But the drugs, discovered at Children's Hospital in Boston in the 1990s, grew out of an idea that dates back much further.

In the early 1970s, Dr. Judah Folkman of Harvard Medical School realized that cancer tumors - clumps of rogue cells that divide uncontrollably - have voracious appetites. He proposed attacking the cancer cells by stopping them from forming the blood vessels they need for nourishment.

Many other scientists were dubious. But 14 years ago, Folkman discovered the first substances that appeared to block blood vessel formation, a process called angiogenesis.

Eventually, Folkman and other Harvard researchers found that two of these substances in particular - proteins called angiostatin and endostatin - can permanently destroy tumors made of human cancer cells when they're transplanted into mice.

Finding these proteins was not a simple task. An important, and pungent, part of the work was done by Dr. Michael O'Reilly, a 34-year-old research associate in Folkman's lab.

Part of his job included straining liters of mouse urine to find trace amounts of angiostatin. The stench of the acrid liquid repelled colleagues and even his wife, who made him air out on the porch each night when he came home.

"It's very fragrant," said O'Reilly. "The problem was the mouse urine has this very musky odor, and it gets on everything, but it was worth it in the end."

Now it's up to EntreMed Inc., a Rockville biotechnology firm, to take the next crucial step: Produce the drugs in large enough quantities to launch clinical trials.

Angiostatin and endostatin do similar but subtly distinct things. Endostatin blocks the activity of proteins that speed growth of blood vessels. Angiostatin stops blood vessels from forming at all.

Alone, each can independently shrink tumors and keep them under control. Together they appear to wipe out several forms of cancer, at least in mice. There are at least a half-dozen other substances that can interfere with the development of blood vessels, said Dr. Bart Chernow, vice dean for research and technology at the Johns Hopkins medical school and an EntreMed founder. Some are already in clinical trials at Hopkins, Georgetown University and elsewhere; dozens of laboratories around the country are testing other substances.

But none, scientists agreed, are as powerful as the combination of endostatin and angiostatin were in mice.

Dr. Louise Grochow of the Johns Hopkins medical school is studying one of three angiogenesis substances now in clinical trials. In the past 10 years, studying these proteins and other compounds has become a fertile area of research. "This is very exciting science. We don't know if it's going to be exciting medicine yet," said Grochow, an associate professor of oncology and medicine. "Of course it's exciting, of course it has great potential, and of course most of us believe it's going to do something," said Dr. Robert Gallo of the Institute of Human Virology in Baltimore, the prominent AIDS researcher who once focused on cancer research.

But there's no telling whether it will kill as many different kinds of tumors as effectively in humans as in mice. Instead, the drugs, like other so-called cancer breakthroughs, may find only limited use against certain forms. Human cancers transplanted into mice don't always act like human cancers that grow spontaneously, Gallo said. Spontaneous tumor cells, for instance, might be hardier and more genetically diverse, more capable of surviving an onslaught of drugs.

Some cancer centers around the country reported many calls yesterday from cancer patients or their families seeking information about the new drugs, but the interest wasn't intense everywhere.

Suzanne Brace, executive director of the Wellness Community, a Towson group that serves cancer patients and their families, said hopes have been raised too often in the past, only to be dashed. Scientists have devised treatments with exotic names like Interferon-alpha, interleukin-2 and TMP 470 that looked FTC exciting when tested on animals. All proved less effective in humans.

"They [cancer patients] hear something, and they immediately respond with, 'Oh my god, this is going to save my life,'" Brace said. "What's so frustrating is that people don't understand science and clinical trials."

Frank Triolo, 65, showed up at the Wellness Community yesterday hoping this latest discovery might be the one that works. He passed out copies of the New York Times articles to others in his family's support group.

"None of the other articles that I ever read said anything about a cure. There's always been control, but not a cure," he said. His wife, Barbara, was diagnosed with colon cancer five years ago. Since then, the Parkville woman has endured three rounds of chemotherapy but the disease has stubbornly hung on, most recently spreading to her brain.

"The oncologist said, 'They're always coming up with new things,'" said Barbara Triolo, 63. After she gets through radiation for her brain tumor, she may go to Buffalo, N.Y., to try a new treatment. "That's what he's been saying for the past year, 'Keep hanging in there.'"

Since a magazine article in 1996 detailed EntreMed's work, patients, physicians and families have deluged the company with more than 100 faxes, e-mails and phone calls a day.

But clinical trials of their would-be wonder drugs are 12 to 18 months off, said R. Nelson Campbell, EntreMed's chief financial officer. The first phase, on healthy human volunteers, is designed only to test whether the drugs are toxic. A larger, second phase would include cancer patients. Campbell said EntreMed does not know who would conduct the study, where it would be staged or how many patients might get the drugs.

Pub Date: 5/05/98

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