Experimental models to evaluate the role of P-glycoprotein in the blood–brain tumor barrier

Abstract

The blood–brain barrier (BBB) is formed by the capillary endothelium in the brain. Tight junctions, low pinocytic activity and lack of fenestrae are hallmarks of this barrier that force compounds to enter the brain by transcellular passage of the endothelial cells. However, many drugs that have appropriate lipophilicity for passive diffusion are a substrate of the multidrug transporter P-glycoprotein (P-gp), which acts as a gatekeeper preventing their entry into the brain. The role of the BBB and of P-gp in the BBB is well established and it is clear it efficiently protects the brain against potentially hazardous substrates. The importance of P-gp in protecting brain tumors, however, is not so well defined yet. In this paper we will discuss our ongoing efforts to resolve this issue. We are developing a panel of experimental brain tumors in mice featuring intact and/or minimally disrupted BBB properties for studying the efficacy of chemotherapy against brain tumors. By using stereotactic implantation of tumor cells into the brain lesions arise with infiltrative, invasive and/or expansive growth characteristics as seen in brain cancer. Tumor cells have been tagged with luciferase to allow convenient non-invasive follow up of tumor burden. To evaluate the role of P-gp we have established colonies of P-gp knockout nude mice and wild-type nude controls to be used as recipients for these xenograft models. We have determined the pharmacokinetic behavior of the model P-gp substrates and potent anticancer drugs paclitaxel and docetaxel, given alone or in combination with P-gp inhibitors. We expect that docetaxel will be most informative on the role of P-gp, because the absence of P-gp does not alter the plasma clearance of this drug.