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At first, he was almost too successful. Everywhere he looked--from cartilage to fungi to the notorious sedative thalidomide--Folkman found one compound after another that exhibited anti-angiogenic properties. But none of them was as effective as he wanted it to be. Then he remembered something that surgeons had often observed: that taking out one big tumor from a patient seems to trigger the growth of lots of smaller ones. Could it be that tumors secrete a substance that inhibits the growth of rival tumors' blood vessels?
It was such a crazy idea that none of the researchers in Folkman's lab wanted anything to do with it. Finally one of them, Dr. Michael O'Reilly, agreed to take on the project. Together he and Folkman eventually determined that various segments of a naturally occurring protein called plasminogen seemed to do the trick. They called the collection of molecular fragments angiostatin and found that each version of the compound differed slightly in its ability to stop a tumor from growing.
But no matter what its configuration, angiostatin could not make a mouse tumor disappear. Not, that is, until Folkman and O'Reilly added to the mix a second molecular fragment, which they called endostatin, from yet another naturally occurring protein. Together, the two compounds destroyed a range of tumors in mice. The results were startling enough that they merited testing in people--which is exactly what Pluda, at the National Cancer Institute, intends to do. How fast those studies can begin depends on how much angiostatin and endostatin EntreMed and its business partner, Bristol-Myers Squibb, can produce and whether they can figure out which fragment to focus on first.
At least Folkman doesn't have to spend all his time nowadays, as he once did, trying to persuade researchers that his approach to cancer treatment has merit. Scientists are currently investigating 300 different substances for their potential to block angiogenesis. Twenty of those compounds have already entered clinical trials in humans. Indeed, researchers suspect that some of the latest cancer treatments, like tamoxifen, may themselves work in part by blocking the growth of newly formed blood vessels.
There are risks involved in messing with the blood vessels. Sometimes angiogenesis is a good thing, especially during pregnancy. One potent anti-angiogenic being studied today is that old scourge thalidomide, which caused so many birth defects in the 1950s by cutting off the blood supply in developing fetuses.
The body also relies on angiogenesis to make new blood vessels during wound healing. That's a particular concern of people with diabetes, whose cuts and abrasions--particularly in their feet--often take a long time to close, leaving them vulnerable to infection. Fortunately they can use a new prescription cream, the first angiogenesis product to win FDA approval, that stimulates the body's repair processes and helps those tiny capillaries in their toes and feet to grow.
And although the newest angiogenesis inhibitors have relatively few side effects, at least compared with radiation or chemotherapy, they are not risk free. "Lack of toxicity in animals does not mean there is no toxicity to humans," says Dr. William Li, medical director of the Boston-based Angiogenesis Foundation, a nonprofit clearinghouse for information on the latest research.