They called his theory ridiculous
Now it's revolutionizing cancer treatmentEvery few years, Dr. Judah Folkman delivers a lecture to Harvard medical students on the difference between obstinacy and persistence. "It's a fine line," he says. "If your idea succeeds, everybody says you're persistent. If it doesn't succeed, you're obstinate." Folkman should know. He has endured the ridicule of critics, who have called him a clown--and worse. And he once watched an auditorium empty when he stood up to give a scientific talk. But the surgeon and cell biologist at Children's Hospital in Boston has never wavered from the deceptively simple-sounding theory he first outlined 25 years ago, a theory that is having profound implications for the treatment of cancer: Tumors need a blood supply in order to grow. As it turns out, Folkman is likely to go down in history as persistent, not merely pigheaded. Over the past decade, the scientist not only has proved his basic premise but in the process has opened a portal on some of cancer's most perplexing secrets. Researchers now understand, for example, that tumors use tricks to induce nearby blood vessels into providing that blood supply by sprouting tiny branches called capillaries. The tumor then uses these capillaries as highways to spread--or metastasize--to far-flung sites in the body. Now, Folkman's lab has produced the most spectacular finding yet: two substances that can cut off a tumor's blood supply, stopping cancer in its tracks. If these drugs work in people as well as they do in mice, they could reverse the deadly odds cancer patients face once their tumors have spread. Folkman's idea rests on the observation that once a tumor grows beyond a few hundred thousand cells--a mass no bigger than a BB--the cells at its center don't get enough blood. To nourish them, the tumor must send out chemical signals that induce capillaries to grow--a process known as angiogenesis, from the Greek angos, for vessel. Finding the switch. Folkman's theory led him to search for biochemical messengers that tumors use to turn on blood vessel cells. In 1983, his lab found the first of these angiogenesis growth factors. Two years later, his team fished out another substance: This one turned off blood vessel cells, slowing the growth of capillaries and--Folkman hoped--some tumors as well. The discoveries turned his critics into competitors. Today, over two dozen pharmaceutical firms are racing to complete clinical trials of nine so-called angiogenesis inhibitors in human patients with a variety of tumors, including cancer of the colon and breast. The drugs are not strong enough to battle cancer alone. Instead, they provide a one-two punch when combined with standard radiation and chemotherapy. The angiogenesis inhibitors starve the tumor by shrinking its blood vessels, while the standard treatment attacks the cancer itself. Recently, Folkman's lab isolated two new factors, called angiostatin and endostatin, which are the most powerful growth inhibitors by far. They also hold out the promise of an entirely new means of battling cancer. Unlike chemotherapy, which can make patients quite ill at high doses, the new factors produce only the mildest of side effects. Indeed, standard chemotherapy makes cancer-ridden mice listless and easy to catch for their daily injections. Those treated with angiostatin and endostatin feel frisky enough to put up a fight. "And I've got the bite marks to prove it," says Dr. Michael O'Reilly, the postdoctoral fellow who discovered the new factors. Drugs based on the new factors also are more likely to keep on working: Cancer cells easily develop resistance to chemotherapy; blood vessel cells, which reproduce more slowly, are more apt to remain susceptible to drugs. For all their promise, these newest angiogenesis inhibitors will not be widely available for human cancer patients anytime soon. For one thing, they are hard to come by. O'Reilly had to collect nearly 3 gallons of mouse urine to purify enough angiostatin to treat a dozen mice. And even when pharmaceutical companies figure out how to make large quantities of the compounds, the drugs must still be tested in human patients, who may not respond as well as mice. None of which can blunt Folkman's excitement. "I've been waiting for results like these my whole life," he says. Last month, Folkman reported that a combination of angiostatin and endostatin eradicated lung tumors in mice for more than five months--the equivalent of 10 years in a human. "The importance of angiogenesis is so obvious when you think about it," says Isaiah Fidler of the M. D. Anderson Cancer Center in Houston. "The world owes Judah Folkman a debt of gratitude."
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