OPENING OF THE BLOOD-BRAIN BARRIER TO ANTITUMOR AGENTS

打开抗肿瘤药物的血脑屏障

• 批准号: 2837592
• 负责人: EDWARD A. NEUWELT
• 金额: $ 24.24万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-02-01 至 2001-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2837592
• 关键词: antineoplastics; blood brain barrier; brain neoplasms; drug delivery systems; human tissue; laboratory rat; neoplasm /cancer chemotherapy; neoplasm /cancer radiation therapy; neoplasm /cancer transplantation; small cell lung cancer

Therapy for brain tumors is complicated by the presence of the blood-brain barrier (BBB), which impedes delivery of chemotherapeutic agents to the central nervous system (CNS). Osmotic BBB disruption (BBBD) is a method to deliver agents through brain and intracerebral tumor. In this proposal, the LX- 1 human small cell lung carcinoma xenograft model in nude rats will be used to examine issues in delivery of antitumor agents to brain tumors and to evaluate the efficacy of therapeutic approaches. The goal of specific aim 1 is to determine why BBD is less consistent in tumor-bearing rat brain then in normal rat brain. We will assess the impact of pharmacologic and physiologic parameters on BBBD in intracerebral tumor-bearing nude rats. This aim is designed to obtain a consistently high percentage of BBBD in experimental animals, will also delineate factors that might be altered in patient BBBD procedures. In specific aim 2 we will investigate the impact of route of chemotherapy administration on therapeutic efficacy. During the past funding period we found intracarotid administration is important for increased drug delivery, but intraarterial delivery in combination with BBBD maximizes drug delivery to tumor-infiltrated areas of brain around the tumor. We will test whether this increased drug delivery is associated with increased anti-tumor efficacy in the nude rat intracerebral tumor model. Specific Aim 3 is to test the effects of sequencing of radiotherapy and BBBD chemotherapy on anti-tumor efficacy in the nude rat model. Their previous studies in normal rats showed that radiation prior to chemotherapy decreased drug delivery to the CNS and increased neurotoxicity compared to the reverse sequence of BBBD chemotherapy prior to radiotherapy. They will test the hypothesis that initial radiotherapy then chemotherapy will also have reduced efficacy. Altogether, the proposed studies are designed to add to our positive record of patient oriented research. Clinical trials, based on previous BBB program preclinical results, have demonstrated that a complete and durable response can be attained in patients with malignant brain tumors, without radiation and without cognitive loss, when delivery is maximized with BBBD. This revised competitive renewal is the continuation of a surgical CREG.

脑肿瘤的治疗因脑肿瘤的存在而变得复杂 血脑屏障(BBB)，阻碍输送 化疗药物对中枢神经系统(CNS)的作用。 渗透性血脑屏障破坏(BBBD)是一种给药的方法 通过脑部和脑内肿瘤。在这份提案中，LX-1 人小细胞肺癌裸鼠移植瘤模型的建立 用于检查抗肿瘤药物脑内给药的问题 并评价各种治疗方法的疗效。 具体目标1的目标是确定为什么BBD较少 在荷瘤大鼠脑中一致，在正常大鼠脑中也一致。我们 将评估药理学和生理学的影响 脑内移植瘤裸鼠BBBD参数的研究 这一目标旨在获得持续较高的百分比 在实验动物中的BBBD，也将描述 可能会在BBBD患者的手术中发生改变。《特定目标2》 我们将调查化疗路线的影响 给药对疗效的影响。在过去的资助中 我们发现颈动脉内给药对 增加药物输送，但联合动脉内给药 BBBD使药物最大限度地输送到肿瘤浸润区 肿瘤周围的脑组织。我们将测试这种增加的药物是否 分娩与提高抗肿瘤疗效有关 裸鼠脑内肿瘤模型。具体目标3是测试 BBBD放疗和化疗序贯治疗的疗效观察 在裸鼠模型中的抗肿瘤作用。他们之前的研究 在正常大鼠身上显示化疗前的放射 减少对中枢神经系统的药物输送，增加神经毒性 与BBBD化疗前的相反顺序相比 放射治疗。他们将检验最初的假设 放疗后再化疗也会降低疗效。 总括而言，建议的研究旨在增加我们的 以病人为中心的研究的积极记录。临床试验，基于 关于之前的BBB计划的临床前结果，已经证明 患者可以获得完全和持久的反应 患有恶性脑瘤，没有放射和没有 认知损失，当使用BBBD最大限度地交付时。这 修订后的竞争性续签是外科手术的延续 克雷格。