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Gleevec May Fight Alzheimer's, Too

Cancer drug shows early promise against the brain disease

MONDAY, Sept. 29, 2003 (HealthDayNews) -- Making a bid to become a sort of medical Swiss Army knife, the cancer-fighting drug Gleevec shows a glimmer of promise at treating Alzheimer's disease, researchers say.

The drug so far has only been tested in guinea pigs and cells in a dish. Whether it works in people remains a mystery. But in the latest study, treatment with Gleevec significantly reduced the buildup in brain cells of harmful proteins that have been linked to Alzheimer's.

A report on the findings appears in this week's online issue of the Proceedings of the National Academy of Sciences.

Gleevec entered the cancer therapy world with great fanfare, its approval revealed in a remarkable announcement by America's top health official in the spring of 2001. Chiefly used against chronic myeloid leukemia, the drug has proven so effective against the blood cancer that it has even been called a cure for the disease. Gleevec, sold by Novartis Pharmaceuticals Corp., also has won U.S. Food and Drug Administration approval to treat a rare form of gastrointestinal tumor.

One of Gleevec's effects is to compete for proteins in cells that bind with ATP, the chemical courier of energy in all living things. As it happens, ATP plays a role in the formation of beta-amyloid, the protein many researchers believe is to blame for the brain cell damage in Alzheimer's disease. The reason: ATP improves the efficiency of an enzyme called gamma-secretase that helps cells produce beta-amyloid.

Preventing the production or buildup of beta-amyloid is now one of the central aims of Alzheimer's research. However, blocking ATP is dangerous business. Done carelessly, it kills cells -- and the bodies they comprise. Gleevec manages to destroy cancer with minimal side effects.

Intrigued, William Netzer, an Alzheimer's expert at the Rockefeller University in New York City, and his colleagues sought to learn if Gleevec could suppress beta-amyloid production.

"We had lots of ATP inhibitors but they're all very toxic," Netzer says. "We felt that if we could inhibit ATP without killing the organism we might be able to inhibit gamma-secretase and inhibit beta-amyloid."

Netzer and his colleagues, who included Nobel Prize winner Paul Greengard, tested the cancer drug in brain cells harvested from rat fetuses, against human beta-amyloid proteins, and in live albino guinea pigs, whose beta-amyloid is akin to what humans produce.

In each case, beta-amyloid levels dropped in cells exposed to Gleevec. The effect increased as the dose of the drug rose -- an important measure of genuine effect -- to as much as a 50 percent reduction compared with untreated cells.

A related experimental drug reduced beta-amyloid 10 times more effectively, Netzer says, but its properties -- including how toxic it is to humans -- aren't yet understood.

There is at least one catch. Gleevec doesn't reach the brain particularly well, barred at the door by the blood-brain barrier, a sort of molecular gate that locks out large molecules. It might be possible to infuse the drug directly into the spinal fluid of Alzheimer's patients, Netzer says. Or perhaps scientists could invent a version of the substance that can penetrate the barrier.

"Most importantly," Netzer says, "we do not yet know whether Gleevec or related compounds will actually help human Alzheimer's patients or whether they will be safe when introduced into the brain."

The researchers' next step is to uncover precisely what protein or proteins Gleevec tweaks that ultimately let it block beta-amyloid buildup. Learning its mechanics could lead to targets for still more treatments for Alzheimer's disease, Netzer says.

Geoffrey Cook, a spokesman for New Jersey-based Novartis, says the drug is currently being tested against a variety of cancers in "about 100" clinical trials. Cook says he isn't aware of any other research looking at Gleevec in a non-cancer disease.

An estimated 4.5 million Americans have Alzheimer's disease. Experts project that number will triple, to 13.2 million, by the year 2050. Early treatment can briefly delay its progression, but there is no cure for the degenerative disease.

More information

To find out more about Alzheimer's disease, visit the Alzheimer's Association. For more on Gleevec, check out Novartis.

SOURCES: William Netzer, Ph.D., research associate, Fisher Center for Research on Alzheimer's Disease, Rockefeller University, New York City; Geoffrey Cook, spokesman, Novartis Pharmaceuticals Corp., East Hanover, N.J.; Sept. 29-Oct. 3, 2003, Proceedings of the National Academy of Sciences
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