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Cancer ‘miracle’ drug Gleevec may also work in Alzheimer’s animal studies suggest
BY JOSEPH BONNER
When Gleevec was swiftly approved by the Food and Drug Administration in 2001, it revolutionized the treatment of a form of leukemia, proving more than twice as effective as existing drugs. Since then, it has also shown exceptional results in the treatment of some types of gastrointestinal cancers. And now, a team of Rockefeller researchers says it may be able to slow the progression of Alzheimer’s disease.
Already, there’s been a lot of excitement surrounding Gleevec. It made front page headlines when it first went on the market two years ago as a treatment for chronic myeloid leukemia; many declared a new era in the treatment of cancer. The reason: Gleevec represents a new class of cancer treatment drugs that work by targeting a mutant enzyme that causes normal cells to become cancerous. Because it’s so specific, Gleevec is generally more effective and causes fewer side effects than more traditional chemotherapy drugs that kill both cancerous and non-cancerous cells.
That Gleevec soon would prove safe and effective for treating people with another form of cancer — gastrointestinal stromal tumors — attracted more headlines. What else could this “miracle drug” combat?
Alzheimer’s disease, theorized a Rockefeller University research team headed by Paul Greengard, Nobel laureate and director of the Fisher Center for Alzheimer’s Disease Research. They theorized that the drug might target related proteins that contribute to the formation of the plaques that characterize Alzheimer’s disease by causing healthy nerve cells to weaken and die.
“We knew that Gleevec binds to at least four enzymes that are distantly related to one another in evolutionary terms, so we took a gamble that there might be more,” explains William Netzer, a research associate in Greengard’s lab who was the first author of a Proceedings of the National Academy of Sciences paper describing the research.
To test their theory, the scientists injected Gleevec into laboratory cultures of brain cells obtained from mice. The drug indeed reduced the buildup of small molecules that lead to the formation of plaques. What’s more, neither Gleevec nor another related compound the scientists studied suffered from the same stumbling block that had ruled out many other promising agents in the treatment of Alzheimer’s — a tendency to interfere with proteins crucial to the body’s immune system.
Taking the research a step further, the Rockefeller researchers, and their colleagues at Memorial Sloan-Kettering Cancer Center, injected Gleevec into the spinal fluid of guinea pigs, whose brain chemistry is similar to that of humans. The results were the same: plaque-forming molecules were reduced in the treated animals.
“The safety of Gleevec, which has already been shown through its use in treating chronic myeloid leukemia and gastrointestinal stromal tumors, combined with its inability to inhibit immune function, make this class of compounds an attractive lead for the development of a potentially safe treatment for Alzheimer’s,” says Greengard, who is a Vincent Astor Professor and a recipient of the 2000 Nobel Prize in Physiology or Medicine.
Whether Gleevec will prove to be uniquely beneficial to people with Alzheimer’s cannot be determined until several kinks are ironed out. The biggest hurdle: The relatively large molecules that make up Gleevec do not cross the blood-brain barrier, the gatekeeper that protects the brain. In the animal studies, Gleevec had to be injected directly into the spinal fluid — a workaround that is obviously less than ideal for humans.
“It’s possible that Gleevec could be chemically modified to cross the blood-brain barrier,” says Netzer. “Or there may be other compounds that function like Gleevec but are chemically suited to enter the brain.”

October 31, 2003



 

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