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: 6773661
• 负责人: DONALD W MILLER
• 金额: $ 23.15万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 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/6773661
• 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脑肿瘤更常见，其特点是治疗选择有限，存活率低。血脑屏障(BBB)通过限制进入大脑的药物数量，导致大多数用于治疗脑肿瘤的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(进入大脑)和向外定向(离开大脑)的运输系统共同影响化疗药物的血脑屏障通透性。在血脑屏障中发现的一个外向转运系统是P-糖蛋白(P-gp)药物外排转运体。这种药物外排转运体还通过限制多种化疗药物的细胞积聚而参与多药耐药。目前的假设是，血脑屏障中存在的P-gp药物外排系统导致许多化疗药物在治疗转移性脑肿瘤方面的疗效有限。进一步的假设是，绕过血脑屏障中的P-gp将增加药物对大脑的输送，并改善治疗脑肿瘤的疗效。为了解决这一假设，将把小鼠乳腺癌细胞(4T1)和小细胞肺癌细胞(3LL)植入具有免疫能力的小鼠的皮下或大脑内。选择化疗药物后的药物蓄积、肿瘤反应和一般神经毒性将在正常条件下和P-gp调节后进行评估。该提案的具体目的是：1)确定化疗药物在正常情况下以及在P-gp被聚合物制剂Pluronic P85或小分子P-gp抑制剂GF918120调节后在大脑中的渗透率。2)评估正常情况下和药物调节P-gp活性后的小鼠肿瘤对化疗药物的反应，以及3)比较P-gp调节后获得的脑瘤反应与使用缓激肽类似物RMP-7短暂、可逆地破坏血脑屏障后观察到的小鼠脑瘤反应。这些研究将对P-gp在所选化疗药物治疗脑瘤有限有效性中的作用进行关键评估。