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December 3, 2001
Find Key To ‘Wasting Syndrome’ Seen In Cancer, AIDS
Scientists in San
Diego pinpointed the biological chain of events that caused wasting in mice,
then identified the same process in liver tissue from cancer patients. They
said the striking similarity between the condition in mice and humans will
expedite the development of new treatments.
“When we saw that it
was virtually identical in animals and humans, we were ecstatic,” said the
study’s senior author, Mario Chojkier, M.D., of the Veterans Affairs (VA)
San Diego Healthcare System and the University of California, San Diego
(UCSD). “What we’ve described in animals has much greater relevance than
we ever thought to human wasting syndrome. We’re optimistic this will bring
hope and relief very quickly to the bedside.”
Dr. Chojkier and lead
author Martina Buck, Ph.D., of VA, UCSD and the Salk Institute for Biological
Studies, described the steps by which tumor necrosis factor (TNF) alpha, an
immune-system protein, prevents the production of albumin. Low levels of
albumin, a critical protein made in the liver, is a keynote of wasting.
TNF-alpha and low
albumin had for years been implicated in wasting, but the connection between
the two was a mystery. Drs. Buck and Chojkier showed that TNF alpha causes
oxidative stress in the liver cell and boosts the production of the
free-radical gas nitric oxide. It also causes the addition of a phosphorous
molecule to a protein called C/EBP beta, which normally joins DNA in the
nucleus of the cell to make other proteins, such as albumin. Central to the
researchers’ finding was that this extra phosphorous causes the C/EBP beta
to shuttle out of the nucleus into the cytoplasm, where transcription from the
albumin gene can no longer take place.
“We found that this
phosphorylation makes the C/EBP beta exit the nuclear area and go into the
cytosol, where there is no DNA for it to bind with. This means it can no
longer produce the protein,” said Dr. Chojkier.
The researchers found
several ways of stopping the downward spiral caused by TNF- alpha. One way was
to treat TNF-alpha-enhanced mice with vitamin E and other antioxidants. This
blocked the chain of events leading to the “nuclear export” of C/EBP beta.
“If we block oxidative stress, we normalize everything,” explained Dr. Chojkier. “C/EBP beta remains in the nucleus, it contacts the DNA, and proteins are produced. Or, if we block the nitric oxide synthase activity, this also blocks the downstream cascade, and everything normalizes.”
According to Dr.
Chojkier, a gastroenterologist and liver specialist, antioxidants such as
vitamin E might halt wasting in humans if these supplements were delivered in
very high amounts—or even better, if they were targeted to the liver.
“One solution will
be to find a liver-specific antioxidant,” he said. “With the technology we
have today, this is very feasible. We believe this will provide an exciting
avenue for intervention.”
Dr. Chojkier also
noted that there are already medications on the market, albeit for different
conditions, that work by preventing phosphorylation, or the addition of a
phosphorous molecule. These drugs could conceivably work in the liver to
restore the normal production of albumin and treat wasting. Drs. Buck and
Chojkier said they hope to test already-available compounds with the goal of
finding one that is safe and effective for wasting.
Catabolic wasting, or
cachexia (ka-kek’-sia), breaks down body tissue, regardless of how much
nutrition the patient absorbs. “It’s like a car that burns too much
fuel,” said Dr. Chojkier. The condition affects about half of all patients
with cancer and AIDS and also affects patients with bacterial and parasitic
diseases, rheumatoid arthritis, and chronic diseases of the bowel, liver,
lungs and heart. Infusions of albumin are occasionally used to treat the
condition, but the treatment is expensive, complicated, and only suitable for
Collaborating on the study with Drs. Buck and Chojkier were Lian Zhang and Nicholas A. Halasz of VA and UCSD, and Tony Hunter of the Salk Institute for Biological Studies. Funding for the study was provided by the Department of Veterans Affairs, the United States Public Health Service and the American Liver Foundation.
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