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

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.