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Increased Permeability of the Blood-Brain Barrier to Chemotherapy in Metastatic Brain Tumors: Establishing a Treatment Paradigm

Elizabeth R. Gerstner, Robert L. Fine

From the Department of Neurology, Neurological Institute of New York; Experimental Therapeutics Program, Division of Medical Oncology, Department of Medicine; and the New York Presbyterian Medical Center, College of Physicians and Surgeons of Columbia University, New York, NY

Address reprint requests to Robert L. Fine, MD, Experimental Therapeutics Program, Columbia University Medical Center, 650 West 168th St, Room 20-05, New York, NY 10032; e-mail: rlf20{at}columbia.edu

There is no accepted standard of care for the chemotherapy treatment of metastatic brain tumors, which has been generally limited to lipophilic alkylators, which may not have efficacy against the tumor that metastasized to the brain. More than 50% of chemotherapy agents are natural product drugs, which are rarely used in the treatment of metastatic brain tumors because they are thought to not cross the blood-brain barrier (BBB). A major protein constituent in the BBB is P-glycoprotein (P-gp), which pumps natural product chemotherapy drugs and toxins out of the CNS. However, P-gp expression in the neovasculature of metastatic brain tumors is similar to the P-gp expression in the neovasculature of the primary, extracranial tumor. In contrast, gliomas have higher P-gp expression in their neovasculature, similar to the greater intrinsic expression of P-gp in normal brain vasculature. This decreased immunohistochemical expression of P-gp in the neovasculature of metastatic tumors, as well as our recent pharmacologic demonstration of increased tissue concentrations of paclitaxel in metastatic brain tumors compared with gliomas, support the idea that the choice of chemotherapy agents should be based on the histologic origin of the metastatic brain tumor and not on the lipophilicity of the drug. Our hypothesis is that metastatic brain tumors from tumors with intrinsically low P-gp expression (eg, lung, melanoma, and untreated breast) may be more permeable to natural product chemotherapy drugs than gliomas. This information could lead to a paradigm shift in the use of natural product drugs for metastatic brain tumors.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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