Metastatic tumors within the central nervous system occur much more frequently than primary brain tumors and are characterized by limited treatment options and low survival rates. The blood-brain barrier (BBB) contributes to the diminished effectiveness of most chemotherapeutic agents used to treat brain tumors by restricting the amount of drug that enters into the brain. Tight junctions between the brain microvessel endothelial cells, together with both inwardly directed (into the brain) and outwardly directed (out of the brain) transport systems influence the BBB permeability of chemotherapeutic agents. One outwardly directed transport system found in the BBB is the P-glycoprotein (P-gp) drug efflux transporter. This drug efflux transporter is also involved in multidrug resistance by limiting the cellular accumulation of a variety of chemotherapeutic agents. The hypothesis of the present proposal is that the P-gp drug efflux transport system present in the BBB contributes to the limited effectiveness of many chemotherapeutic agents in the treatment of metastatic brain tumors. It is further hypothesized that circumventing P-gp in the BBB will increase drug delivery to the brain and improve therapeutic outcomes in treating brain tumors. To address this hypothesis, murine breast cancer cells (4T1) and murine small cell lung cancer cells (3LL) will be implanted, either subcutaneously or intracerebrally, into immunocompetent mice. Drug accumulation, tumor responsiveness and general neurotoxicity following selected chemotherapeutic agents will be evaluated under normal conditions and following P-gp modulation.
The Specific Aims of the proposal are to: 1) determine chemotherapeutic drug penetration in the brain under normal conditions and following P-gp modulation with either polymer formulation, Pluronic P85, or the small molecule P-gp inhibitor, GF918120. 2) evaluate tumor responses to chemotherapeutic agents in mice under normal conditions and following pharmacological modulation of P-gp activity, and 3) compare brain tumor responses obtained following P-gp modulation with those observed in mice following transient, reversible disruption of the BBB with the bradykinin analog, RMP-7. These studies will provide a critical assessment of the role of P-gp in the limited effectiveness of selected chemotherapeutic agents in treating brain tumors.
