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A medical detective mystery

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http://www.nctimes.com/articles/2006/08 ... 8_3_06.txt

By: BRADLEY J. FIKES - Staff Writer

How is macular degeneration like cancer? The question sounds like one of those inside medical jokes, but the answer was developed out of profound scientific insight. Both diseases depend upon the abnormal growth of new blood vessels. So a drug that stops blood vessel growth, called angiogenesis, should be effective in both diseases.

That insight began with Judah Folkman, a brilliant doctor and researcher at Harvard Medical School and Children's Hospital in Boston. More than four decades ago, Folkman thought of a clever way to outwit cancer by starving it of the blood-carried nutrients cancer cells needed to grow.

Acting on meager clues like a medical Sherlock Holmes, Folkman deduced that cancers grew because they secreted chemicals that encouraged angiogenesis. So, he reasoned, it should be possible to slow or stop the growth of cancers with an angiogenesis-blocking compound.

The idea got a chilly reception from many cancer researchers, and Folkman labored for many years to accumulate the evidence to confirm his deduction. By the early 1980s, a research team led by Folkman had identified the first of his previously hypothetical molecules that encourage angiogenesis.

They then discovered a compound that blocked this molecule. It took years more before the first angiogenesis-blocking drug, endostatin, was ready for testing by the biotechnology company EntreMed Inc.

It took more years to firmly establish the usefulness of angiogenesis therapy. Trials of endostatin yielded disappointing results, and it was called a flop. In 2003, EntreMed, the only U.S. maker of endostatin, stopped making it due to financial problems. In 2005, endostatin was approved for sale in China after positive clinical trials.

But Folkman and his colleagues doggedly continued their work. It turned out that several compounds are involved in angiogenesis, and understanding how they work is critical to making them effective. And some anti-cancer drugs were found to have previously unknown anti-angiogenic properties, helping to explain their effectiveness.

Avastin's role

Enter another anti-cancer, anti-angiogenesis drug, called Avastin. Made by Genentech, Avastin blocks the action of VEGF, or vascular endothelial growth factor. Technically, Avastin is a monoclonal antibody, Antibodies are large protein molecules made by the body's disease-fighting immune system. They latch onto targets, typically invading microbes. A monoclonal antibody is a mass-produced copy of one kind of antibody that attacks one specific target, in this case, VEGF, neutralizing it.

Avastin has been found effective against metastatic colorectal cancer, and is being tested for non-small cell lung cancer, breast cancer, ovarian cancer, and other cancers. For more information, search for Avastin at www.clinicaltrials.gov.

In another detective leap, researchers reasoned that anti-angiogenesis drugs might help treat age-related "wet" macular degeneration. The most severe form of this disease, it is also caused by abnormal blood vessel growth. Blood vessels grow under the retina, leaking and slowly blocking vision.

Although Avastin was not approved for this use, some doctors began prescribing it anyway as an "off-label" use, which they have the right to do. One motive was cost: The amount of Avastin needed for treating wet macular degeneration is a fraction of that needed for cancer.

Doctors found anecdotal evidence of good results, backed up by a June 2005 study in the journal Ophthalmology. It reported "significant increases" in visual acuity within one week, and within 12 weeks, an increased ability to read letters. There were no serious problems reported.

Unlike Avastin, Lucentis is specifically designed to treat wet macular degeneration. It's a protein molecule derived from a fragment of Aventis. In clinical studies, 40 percent of patients getting Lucentis achieved 20/40 vision or better. Also, 95 percent of patients at least experienced no additional deterioration of vision.

Contact staff writer Bradley J. Fikes at bfikes@nctimes.com or (760) 739-6641.

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