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. Schuetz 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
Contact: Bonnie Cameron
St. Jude Children's Research Hospital