BOSTON (AP) -- Dr. Judah Folkman's mice are growing old and gray, famously cured of cancer. But people? Not yet and probably not real soon.

Developing new cancer treatments is a notoriously frustrating endeavor. Failure is the norm. Any medicine that stretches survival just a couple of months is considered a victory.

But even by the incremental pace of this field, exploiting Folkman's invitingly simple idea for stopping cancer - just shut off the blood supply - has been slow going.

So far, six medicines based on his theory have finished the final rounds of human testing. Each medicine was given to hundreds of terminal cancer patients. And each failed to help in any meaningful way.

Eleven more drugs are moving through large-scale studies. Although all seem promising enough to bring to this expensive stage of testing, no one knows how well any of them will work, if at all.

Even if one or more of these eventually reaches the market - which is possible in the next two to three years - none is likely to be The Cure. That unlikely hope flourished four years ago, but has largely faded as reality sinks in.

This is cancer, after all, a disease that many doubt will be tamed by a single new medicine.

However, that was exactly the hope some had for Folkman's insight. His medicines and many others based on his research are designed to stop angiogenesis, the formation of new blood vessels that are necessary for tumors to grow larger than a pinhead. Without a fresh blood supply, the thinking goes, cancer stops in its tracks.

Those who still believe Folkman made a wonderful discovery say early disappointments are to be expected in a brand new field. But they wonder if the discovery will be written off because of unrealistic expectations it will yield treatments dramatically better than the usual results of science's progress - cancer medicines that sometimes work somewhat in some people.

"People have pretty much discounted the field," says Dr. Gwen Fyfe, Genentech's senior director of oncology. "There are waves of popularity and then disgust. We are in the wave of disgust for antiangiogenic drugs, and it's just as inappropriate as the wave of hysteria was."

That hysteria erupted in May 1998. Folkman had been working in obscurity for three decades at Boston's Children's Hospital, exploring tumor blood vessel growth in mice. After an astonishing quote in a newspaper story, he abruptly became the most famous cancer scientist in the world, his work on the covers of newsweeklies and the talk of network news.

The quote in the front page article in the Sunday New York Times from Dr. James Watson, the Nobel laureate and co-discoverer of the shape of DNA said: "Judah is going to cure cancer in two years."

Watson, however, is not a cancer specialist, and many ridiculed the idea that a single treatment of any kind would cure all kinds of cancer. Watson himself backed off.

Still, the idea was planted.

Folkman's lab had discovered two natural compounds, called endostatin and angiostatin, that appeared to be powerful cancer fighters, at least in lab mice. When the mice were given the drugs, their tumors shrank up and disappeared.

These days, Folkman says, "We have dozens of mice downstairs that are getting old and gray because they had cancer, and we treated them. Some have been on endostatin their whole lives, and they're fine."

But as he and others point out, the mice's tumors are much easier to cure than those in humans. Countless compounds that have been promising in the lab have turned out ineffective in people.

Proving that a new medicine makes a difference at all against cancer can be difficult. In part, this is because testing typically starts on the terminally ill after their spreading cancer fails all standard treatment.

But the challenge may be particularly great for angiogenesis blockers. These drugs are not designed to kill cancer, so their benefits may be subtle and slow to emerge. Because the drugs are being tested like regular chemotherapy, which involves giving the biggest possible dose and looking for quickly shrinking tumors, many worry that some blood vessel blockers have been dismissed too soon.

Instead of shrinking cancer, these drugs may stop it from growing, turning cancer into a stable, manageable disease, like diabetes.

Moreover, the first step in testing ordinary chemotherapy is to check for the maximum tolerated dose - the amount that stops just short of killing the patient. But many of the blood vessel blockers have no ill effects at all, so doctors are unsure what dose to take to the next stage of testing.

So far, no one has found an easy-to-read indicator, such as a blood test, that might quickly reveal the drugs' effectiveness inside the body.

"The problem is, how do you develop a drug when you don't really know how it works, don't know how to administer it and are not sure how to measure it?" asks Dr. Adam Dicker, a radiation oncologist at Jefferson Medical College in Philadelphia.

Without the attention four years ago, these blood vessel blockers would probably succeed or fail out of public view, especially in the early safety phase.

But after Folkman's celebrity, demand for his untested drugs was overwhelming, especially for endostatin, the first to leave the lab in 1999.

At Boston's Dana-Farber Cancer Institute, one of four hospitals in the United States and Europe to do the first-stage safety testing, about 1,700 people asked for a chance at endostatin. Eventually 25 were chosen.

"It was guaranteed to be disappointing," says Dana-Farber's Dr. J. Paul Eder. "The whole field has suffered in part by all of the very unreasonable expectations, much of which was endostatin-driven."

The study was never intended to answer whether endostatin works, although doctors looked for an effect.

Of 94 patients with 18 different kinds of cancer, five seemed to be helped, at least somewhat. Tumors shrank modestly in three, while in two others cancer receded in some places and advanced in others. Two of those who did best had rare tumors of the insulin-producing tissue in the pancreas.

Nevertheless, the results settled one issue. This was not The Cure, at least, not for everyone with terminal cancer.

"The hypothesis was that this should work for every cancer. Well, it doesn't," says Eder, although the drug "shows some glimmer of promise" and appears safe.

This was not what many had hoped to see.

"Were the results disappointing? Sure they were. They were especially disappointing for the patients who were not helped," says Dr. Paul Bunn, director of the University of Colorado Cancer Center and president of the American Society of Clinical Oncology.

In November, doctors began testing endostatin against insulin cell tumors. Eventually, 40 patients will get the drug at Dana-Farber and the University of California, San Francisco. A study of angiostatin's effectiveness against lung cancer is expected later this year.

Folkman believes that because these drugs work slowly, they will show their greatest benefit in patients with less advanced disease. "We haven't even gotten to where we can give endostatin and angiostatin together, which is where in our papers we saw fast regression."

Many doubt that blocking angiogenesis will be enough. Dr. Michael O'Reilly of M.D. Anderson Cancer Center in Houston who discovered endostatin and angiostatin while in Folkman's lab, predicts these drugs will have to be combined with other treatments, such as standard chemotherapy.

"Angiogenesis inhibitors should never be considered a magic bullet, meaning you take a single pill and your cancer goes away forever," he says.

One reason: Cancers need growth proteins to sprout blood vessels, and these change over time. At first, just one protein may do the job. But as cancers mature, they become sensitive to more and more growth proteins - at least 15 are known - and shutting off all of them is a huge challenge.

Several of the drugs that failed early testing were designed to block an enzyme the cancer needs to eat out channels for new blood vessels. Why this did not work is still unclear. Many of the current crop are aimed squarely at the growth proteins, especially a common one called vascular endothelial growth factor, or VEGF.

Among the farthest along in testing is Genentech's Avastin, which appeared to slow cancer progression in early testing. Large-scale studies are under way in breast and colon cancer, and the first results could be out in the fall.

Another high-profile drug aimed at VEGF, Pharmacia's SU5416, was scrapped in February when a large colon cancer study found no benefit.

Dr. William Li of the nonprofit Angiogenesis Foundation says more than 200 companies are in the field, and more than 300 potential blood vessel blockers have been discovered so far. At least 40 have entered human cancer testing, although totals are murky because some drugs get counted even though they also fight cancer in other, perhaps more important ways.

"The concept is great. The science is great," says Dr. Gerald Soff of Northwestern University. "Like everything in medicine and cancer in particular, it takes time."

Copyright 2002 The Associated Press. All rights reserved.