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

Abstract

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.