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).
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Contact: Bonnie Cameron
bonnie.cameron@stjude.org
901-495-4815
St. Jude Children's Research Hospital
10-Oct-2004