Protein Protects Brain Tumors From Therapy

Cancer researchers have found that the Mrp4 protein acts to prevent the chemotherapeutic drug topotecan from reaching cancer cells in the brain.

Investigators at St. Jude Children's Research Hospital (Nashville, TN, USA) genetically engineered a mouse line lacking the gene for Mrp4. They found that contrary to the situation in normal mice, topotecan injected into the blood stream of these animals readily crossed the blood-brain barrier and accumulated in brain tissues (choroid plexus) and in the cerebrospinal fluid (CSF).

The investigators used new antibodies to show that Mrp4 was unique among the anionic ATP-dependent transporter proteins in that it was localized both at the basolateral membrane of the choroid plexus epithelium and in the apical membrane of the endothelial cells of the brain capillaries. This placement allowed Mrp4 to both inhibit transport of topotecan and to transport back any molecules that did penetrate the blood-brain barrier. These findings were published in the September 2004 issue of Molecular and Cellular Biology.

"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 [central nervous system] tumors,” said senior author Dr. John Scheutz, associate member of the department of pharmaceutical sciences at St. Jude Children's Research Hospital. "Our work has important implications for therapies that target brain tumors with specific types of drugs that are transported by Mrp4. 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.”




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