Influence of P-glycoprotein in treating brain tumors

P-糖蛋白在治疗脑肿瘤中的作用

• 批准号: 7123661
• 负责人: DONALD W MILLER
• 金额: $ 17.01万
• 依托单位: UNIVERSITY OF MANITOBA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7123661
• 关键词: P glycoprotein; antineoplastics; blood brain barrier; brain neoplasms; breast neoplasms; carmustine; disease /disorder model; doxorubicin; laboratory mouse; lung neoplasms; melphalan; metastasis; neoplasm /cancer pharmacology; neurotoxicology; paclitaxel; pharmacokinetics; protein structure function; vascular endothelium permeability

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.

描述（由申请人提供）：中枢神经系统内的转移性肿瘤比原发性脑肿瘤发生频率高得多，其特征是治疗选择有限和生存率低。血脑屏障（BBB）通过限制进入大脑的药物量而导致用于治疗脑肿瘤的大多数化疗药物的有效性降低。脑微血管内皮细胞之间的紧密连接，以及向内定向（进入脑）和向外定向（离开脑）的转运系统影响化疗剂的BBB渗透性。在血脑屏障中发现的一种外向转运系统是P-糖蛋白（P-gp）药物外排转运蛋白。这种药物外排转运蛋白也通过限制多种化疗药物的细胞积累而参与多药耐药性。本建议的假设是，存在于BBB中的P-gp药物外排转运系统导致许多化疗剂在治疗转移性脑肿瘤中的有效性有限。进一步假设，绕过BBB中的P-gp将增加药物向脑的递送并改善治疗脑肿瘤的治疗结果。为了解决这一假设，将鼠乳腺癌细胞（4 T1）和鼠小细胞肺癌细胞（3LL）皮下或脑内植入免疫活性小鼠中。将在正常条件下和P-gp调节后评价选定化疗药物的药物蓄积、肿瘤反应性和一般神经毒性。该提案的具体目的是：1）在正常条件下和用聚合物制剂Pluronic P85或小分子P-gp抑制剂GF 918120调节P-gp后，测定脑中的化疗药物渗透。2)评价在正常条件下和在药理学调节P-gp活性后小鼠中对化疗剂的肿瘤应答，和3）比较在P-gp调节后获得的脑肿瘤应答与在用缓激肽类似物RMP-7短暂、可逆破坏BBB后小鼠中观察到的脑肿瘤应答。这些研究将对P-gp在所选化疗药物治疗脑肿瘤的有限有效性中的作用进行重要评估。