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    Clinton F. Stewart, PharmD

    Clinton F. Stewart, PharmD

    Scientists gain new insight into drug pump in brain

    St. Jude researchers have found evidence in a mouse model that simultaneous therapy with a drug that regulates movement of topotecan from the bloodstream can reduce its concentration in the cerebrospinal fluid (CSF). CSF is the watery substance that fills the interconnected series of spaces—ventricles—within the brain. The finding is important because the most common childhood brain tumors occur near the CSF-filled spaces of the brain.

    Anything that prevents anticancer drugs from moving from the bloodstream to the CSF would reduce the exposure to anticancer drugs in this fluid, thus reducing the amount of the drug that reaches the tumor.

    In order for anticancer drugs administered through veins to leave the bloodstream and pass into the brain, they must pass across either of two membrane barrier systems, according to Clinton Stewart, PharmD, Pharmaceutical Sciences. The blood-brain barrier regulates drug movement into the area surrounding brain cells; and the blood-CSF barrier regulates movement from blood to the CSF. Stewart is senior author of a report on this work that appears in the December 1, 2006, issue of Cancer Research.

    The team first found that only a small amount of topotecan injected into mouse veins was able to penetrate the brain’s extracellular fluid, but a large amount of the drug made it into the CSF. So they pretreated the mice with gefitinib, which is known to regulate drug pumps of the brain barriers, and then injected topotecan into their veins. The team found that the amount of topotecan slipping through the blood-brain barrier increased, as would be expected if gefitinib blocked the pump.

    But the amount of topotecan that made it into the CSF decreased. The investigators explained their observations by reporting for the first time the presence in mice of a specific drug transporter called BCRP on the membranes of cells making up the choroid plexus—the structure that makes CSF.

    “If we find humans have BCRP at the blood-CSF barrier, our findings will have implications for the treatment of children with brain tumors that occur near the CSF-filled spaces,” said Yanli Zhuang, PhD, a graduate student in Stewart’s laboratory who did much of the work on this project. “If so, this pump moves topotecan out of the blood and into the CSF,” she added. “Gefitinib might block this pump in humans, reducing the amount of Topotecan that reaches the tumors through the CSF. This is something for clinicians to keep in mind when they design treatments for such tumors that include the use of gefitinib.”

    Other St. Jude authors include Pharmaceutical Sciences employees Charles Fraga, Elaine Hubbard, Nikolaus Hagedorn and John Panetta, PhD.

    January 2007