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: 7022920
• 负责人: DONALD W MILLER
• 金额: $ 10.47万
• 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 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7022920
• 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得更频繁，其特点是治疗选择有限且存活率低。血脑屏障 (BBB) 通过限制进入大脑的药物量，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（进入大脑）和向外（离开大脑）的运输系统会影响化疗药物的血脑屏障通透性。 BBB 中发现的一种向外定向的转运系统是 P-糖蛋白 (P-gp) 药物外排转运蛋白。这种药物外排转运蛋白还通过限制多种化疗药物的细胞积累来参与多药耐药性。本提议的假设是，BBB 中存在的 P-gp 药物外排转运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 BBB 中的 P-gp 将增加药物向大脑的输送，并改善脑肿瘤的治疗效果。为了解决这一假设，小鼠乳腺癌细胞（4T1）和小鼠小细胞肺癌细胞（3LL）将被皮下或脑内植入免疫活性小鼠体内。将在正常条件下和 P-gp 调节后评估选定化疗药物后的药物蓄积、肿瘤反应性和一般神经毒性。该提案的具体目标是：1) 确定正常条件下化疗药物在使用聚合物制剂 Pluronic P85 或小分子 P-gp 抑制剂 GF918120 进行 P-gp 调节后在大脑中的渗透情况。 2) 评估小鼠在正常条件下和 P-gp 活性药理学调节后肿瘤对化疗药物的反应，以及 3) 将 P-gp 调节后获得的脑肿瘤反应与用缓激肽类似物 RMP-7 短暂、可逆破坏 BBB 后在小鼠中观察到的脑肿瘤反应进行比较。这些研究将对 P-gp 在所选化疗药物治疗脑肿瘤的有限疗效中的作用提供关键评估。

项目成果

Examination of blood-brain barrier (BBB) integrity in a mouse brain tumor model.

• DOI: 10.1007/s11060-012-1006-1
• 发表时间: 2013-01
• 期刊: JOURNAL OF NEURO-ONCOLOGY
• 影响因子: 3.9
• 作者: On, Ngoc H.;Mitchell, Ryan;Savant, Sanjot D.;Bachmeier, Corbin. J.;Hatch, Grant M.;Miller, Donald W.
• 通讯作者: Miller, Donald W.