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的发生频率要高得多，其特征是治疗选择有限和存活率较低。血脑屏障（BBB）通过限制进入大脑的药物量来治疗脑肿瘤的大多数化学治疗剂的有效性降低。大脑微血管内皮细胞之间的紧密连接，以及向内的（进入大脑）和向外定向（向外（向外）转运系统）会影响化学治疗剂的BBB渗透性。在BBB中发现的一个外向转运系统是P-糖蛋白（P-GP）药物外转运蛋白。该药物外排转运蛋白还通过限制各种化学治疗剂的细胞积累来参与多药耐药性。本提案的假设是，BBB中存在的P-gp药物外排运输系统有助于许多化学治疗剂在治疗转移性脑肿瘤中的有限效率。进一步假设，BBB中规避P-gp将增加药物输送到大脑，并改善治疗脑肿瘤的治疗结果。为了解决这一假设，鼠乳腺癌细胞（4T1）和鼠小细胞肺癌细胞（3LL）将被植入皮下或脑内植入免疫能力的小鼠中。在正常条件下和P-gp调节后，将评估选定化学治疗剂后药物积累，肿瘤反应性和一般神经毒性。该提案的具体目的是：1）在正常条件下确定大脑中的化学治疗药物渗透，并在P-gp调制后使用聚合物配方Pluronic P85或小分子P-GP抑制剂GF918120确定化学治疗药物。 2）评估在正常条件下和药理学调节P-gp活性的小鼠中对肿瘤对化学治疗剂的反应，以及3）比较P-gp调节后在P-gp调节后获得的脑肿瘤反应与在短暂的小鼠中观察到的脑肿瘤反应，而在短暂的，可逆的BBB中，BBB与Bradykininagin Abalog，RMP-7进行了可逆性破坏。这些研究将对P-gp在选定的化学治疗剂治疗脑肿瘤中的有限有效性中的作用进行批判性评估。