Influence of P-glycoprotein in treating brain tumors

描述（由申请人提供）：中枢神经系统转移性肿瘤比原发性脑肿瘤发生得更频繁，其特点是治疗选择有限，生存率低。血脑屏障（BBB）通过限制进入大脑的药物量，降低了大多数用于治疗脑肿瘤的化疗药物的有效性。脑微血管内皮细胞之间的紧密连接，以及向内（进入大脑）和向外（离开大脑）的运输系统影响化疗药物血脑屏障的通透性。在血脑屏障中发现的一个向外定向转运系统是p -糖蛋白（P-gp）药物外排转运体。这种药物外排转运体也通过限制多种化疗药物的细胞积累而参与多药耐药。本提案的假设是，血脑屏障中存在的P-gp药物外排运输系统导致许多化疗药物在治疗转移性脑肿瘤时效果有限。进一步假设绕过血脑屏障中的P-gp将增加药物向大脑的输送，并改善治疗脑肿瘤的治疗效果。为了验证这一假说，研究人员将小鼠乳腺癌细胞（4T1）和小鼠小细胞肺癌细胞（3LL）皮下或脑内植入具有免疫功能的小鼠体内。将在正常条件下和P-gp调节后评估选定化疗药物的药物积累、肿瘤反应性和一般神经毒性。该提案的具体目的是：1)确定在正常条件下化疗药物在大脑中的渗透，并使用聚合物制剂Pluronic P85或小分子P-gp抑制剂GF918120进行P-gp调制。2)评估正常条件下和P-gp活性药理调节下小鼠肿瘤对化疗药物的反应，3)比较P-gp调节后获得的脑肿瘤反应与缓激肽类似物RMP-7短暂可逆破坏血脑屏障后小鼠的脑肿瘤反应。这些研究将为P-gp在选定的化疗药物治疗脑肿瘤的有限有效性中所起的作用提供关键评估。

DESCRIPTION (provided by applicant): 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.