| JWissmille 2004-10-24, 2:08 am |
| http://news.biocompare.com/newsstory.asp?id=53584
Protein That Protects Brain From Toxins Also Blocks Some Chemotherapy From
Reaching Tumors
10/10/2004
Source: St. Jude Children's Research Hospital
A protein called Mrp4 blocks the access of the anti-cancer drug topotecan into
the brain by transporting this agent back into the bloodstream, thus reducing
the ability of this agent to reach tumors. Results from a series of studies by
investigators at St. Jude Children's Research Hospital are published in a
recent issue of Molecular and Cellular Biology (MCB).
The St. Jude team, which developed a mouse model lacking the Mrp4 protein, says
study results in both mice and tissue cultures suggest that the therapeutic
efficacy of drugs targeting central nervous system tumors might be improved by
inhibiting this protein, a type of molecule called an ABC- dependent
transporter.
The study showed that Mrp4 works at two levels: by binding to topotecan and
transporting it away from the brain Mrp4 restricts the drug's penetration into
the brain from the bloodstream; and it protects brain cells from accumulating
toxic levels of topotecan molecules that do escape the bloodstream.
"The ability of Mrp4 to protect the brain from toxins can be a liability in
people with brain cancer when this protein also blocks therapeutic drugs from
reaching CNS tumors," said John Scheutz, Ph.D., an associate member of the St.
Jude Department of Pharmaceutical Sciences. Scheutz is senior author of the
article.
The investigators discovered that when topotecan was injected into the veins of
specially bred mice that lack Mrp4, the drug accumulated to greater than normal
levels in the brain tissue and the fluid that surrounds the brain -- the
cerebrospinal fluid (CSF).
The finding strongly suggests that the natural role of Mrp4 is to block the
passage of certain toxic molecules, which chemically resemble topotecan, from
leaving the bloodstream and entering the brain. The cells lining the walls of
brain capillaries are tightly joined to form a barrier that prevents most
substances from leaving the blood. This cellular barrier, called the
blood-brain barrier, prevents certain substances from leaving the bloodstream
and entering the brain. Mrp4 in the blood-brain barrier also prevents
substances from entering the brain by transporting them back into the blood as
they pass into the cells of this barrier.
Using antibodies against Mrp4 the investigators found that this protein is
located in the brain's capillaries as well as in membranes of the choroid
plexus -- the folds within the brain ventricles that make and release CSF.
"This dual location for Mrp4 is unusual for this type of transporter," Schuetz
said. "It suggests that Mrp4 blocks specific molecules from leaving the
capillaries. And if such molecules slip out of the blood into the choroid
plexus, Mrp4 shuttles them back out of the brain and into the blood before they
can cause damage."
The investigators also showed that isolated cells that were modified to
over-express Mrp4 did not accumulate as much topotecan as cells lacking this
protein. This is strong evidence that over-_expression of Mrp4 in tumors
contributes to topotecan resistance in patients.
"Our work has important implications for therapies that target brain tumors
with specific types of drugs that are transported by Mrp4," Schuetz said.
"There is an expanding array of these types of drugs being developed; and
unless there is a way to block Mrp4 when giving these agents, the effectiveness
of these new agents could be significantly compromised."
Other authors of this study are Markos Leggas, Masashi Adachi, Daxi Sun,
Guoqing Du, Kelly E. Mercer, Yanli Zhuang, John C. Panetta, Brad Johnston and
Clinton F. Stewart (St. Jude); George L. Scheffer and Rik J. Scheper (VU
Medical Center, Amsterdam, The Netherlands); and Peter Wielinga (The
Netherlands Cancer Institute, Amsterdam).
This work was supported in part by NIH, a Cancer Center Support Grant, the
Dutch Cancer Society and ALSAC.
St. Jude Children's Research Hospital
St. Jude Children's Research Hospital is internationally recognized for its
pioneering work in finding cures and saving children with cancer and other
catastrophic diseases. Founded by late entertainer Danny Thomas and based in
Memphis, Tennessee, St. Jude freely shares its discoveries with scientific and
medical communities around the world. No family ever pays for treatments not
covered by insurance, and families without insurance are never asked to pay.
St. Jude is financially supported by ALSAC, its fundraising organization. For
more information, please visit http://www.stjude.org/ .
CONTACT: Bonnie Cameron, APR of St. Jude Public Relations,+1-901-495-4815,
bonnie.cameron@stjude.org, or Marc Kusinitz, Ph.D., St. JudeScientific
Communications, +1-901-495-5020, marc.kusinitz@stjude.org, both forSt. Jude
Children's Research Hospital
Web site: http://www.stjude.org/
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