Introduction Paclitaxel (Taxol) and derivatives are active against various tumors (1-6) and have also been used to treat malignant glioma and brain metastases (7-9). However, brain tumors constitute a difficult problem and the therapeutic benefit of paclitaxel has been variable and low. This could be attributed to its limited entry into the CNS. Although paclitaxel is very lipophilic, concentrations in the CNS are very low after intravenous administration (10, 11). Paclitaxel appears to be a substrate of the multidrug resistance protein p-gp (12-14), and it is likely that this transporter contributes to its limited access to the brain. P-gp is expressed in high levels in cultured brain capillary endothelial cells and in intact brain capillaries (15, 16). It is localized at the luminal surface of the endothelium (17, 18), and therefore is in the correct location to restrict permeation of a variety of drugs into the CNS (19-21). Animals with reduced p-gp function show an accumulation of p-gp substrates in the brain as well as a markedly increased sensitivity to neurotoxic p-gp substrates, e.g., ivermectin (18, 22, 23). The present study identifies in vitro a mechanism that limits paclitaxel access to the CNS and outlines a strategy to circumvent it by blocking p-gp. We demonstrated that the p-gp blocker valspodar enhances paclitaxel entry into the brains of mice after intravenous dosing and that valspodar dramatically increases paclitaxel effectiveness against a human glioblastoma implanted into the CNS of nude mice. These are the first data directly demonstrating the role of p-gp in limiting the therapeutic availability of paclitaxel to the CNS. Methods Chemicals. Valspodar (SDZ PSC 833) and the fluorescent cyclosporin derivative NBDL-CS were from Novartis Pharma GmbH