OPENING OF THE BLOOD-BRAIN BARRIER TO ANTITUMOR AGENTS

打开抗肿瘤药物的血脑屏障

• 批准号: 2088202
• 负责人: EDWARD A. NEUWELT
• 金额: $ 19.26万
• 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 1996-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2088202
• 关键词: antineoplastics; antitumor antibody; blood brain barrier; brain neoplasms; chelating agents; cis platinum compound; combination chemotherapy; combination therapy; contrast media; doxorubicin; drug delivery systems; electroencephalography; etoposide; gadolinium; human tissue; immunoconjugates; immunoglobulin G; immunoglobulin structure; iodine; laboratory rat; lung neoplasms; magnetic resonance imaging; methotrexate; mitomycins; monoclonal antibody; neoplasm /cancer chemotherapy; neoplasm /cancer immunotherapy; neoplasm /cancer radiation therapy; neoplasm /cancer radionuclide therapy; neoplastic cell; neurotoxins; nonhuman therapy evaluation; prodrugs; radionuclide imaging /scanning; radionuclides; radiotracer; toxicology

In the current proposal, monoclonal antibodies (IgG and F(ab')2) will be combined with BBB disruption to target chemotherapeutic drugs, radionuclides and paramagnetic MRI agents to intracerebral and subcutaneous tumor in nude rats. In these studies, we are combining knowledge obtained during the early years of this R01 proposal with more recent information on antibody delivery and localization to now evaluate therapy, toxicity, and efficacy with antibody targeting. These targeting studies will focus on four delivery systems. First, the L6 antibody conjugated to alkaline phosphatase will be delivered to the LX-1 tumor with BBBD. Subsequently, the administration of phosphorylated chemotherapeutic agents such as mitomycin phosphate will be activated primarily at the site of the tumor by the extracellular alkaline phosphatase covalently linked to the L6 antibody bound to the cell surface. In a second approach, a modulating antibody conjugated to adriamycin will be evaluated. Third, using an effective chelating system that tightly binds radiolabels, localization and efficacy studies will compare gamma- and beta-emitters chelated to the L6 antibody. To date the L6 antibody has been evaluated using either radioiodination or immunohistology. Finally, using the same chelating systems to attach radiolabels to the L6 antibody, paramagnetic substances, such as gadolinium, will be chelated to combine the spatial resolution of MRI with the biologic specificity of localizing monoclonal antibodies such as L6. Associated with these studies will be the neurotoxicity testing of gadolinium contrast agents with vastly differing dissociation constants. The second area to be emphasized in this competitive renewal is the toxicity and efficacy of chemotherapeutic agents administered with and without osmotic BBB disruption before, concomitant with and after external beam radiotherapy. The two least toxic and most efficacious chemotherapeutic combinations in our clinical studies have been methotrexate and cytoxan and more recently the combination of carboplatin and etoposide. The efficacy of these combinations will be evaluated in our nude rat tumor model using the LX-1 human lung carcinoma. In addition, because of past successes in testing the neurotoxicity of chemotherapeutic agents administered with disruption in animals for potential clinical use, we will similarly investigate several new agents. Efficacy will be evaluated not only by survival but also tumor volumetric measurements to assess response both histologically and by serial MRI in vivo scanning. Neurotoxicity testing has a new evaluation dimension in our ability to measure EEG in animals. Our overall objective is to continue to improve delivery of antitumor agents and imaging agents to brain tumors and, finally, to evaluate efficacy of therapeutic approaches. This proposal is in response to the program announcement in surgical oncology and is a continuation of a surgical CREG.

在目前的提议中，单抗(Ig G和F(ab‘)2)将是 结合对血脑屏障的干扰来靶向化疗药物， 放射性核素和顺磁MRI试剂对脑内和 裸鼠皮下移植瘤。在这些研究中，我们结合了 在本R01提案的最初几年中获得的知识，以及更多 关于抗体传递和定位的最新信息现在进行评估 抗体靶向的治疗、毒性和疗效。这些目标 研究将集中在四种传递系统上。第一，L6抗体 结合碱性磷酸酶将被运送到LX-1肿瘤 和BBBD一起。随后，给药的磷酸化 磷酸丝裂霉素等化疗药物将被激活 主要由细胞外碱性物质作用于肿瘤部位 与细胞结合的L6抗体共价连接的磷酸酶 浮出水面。在第二种方法中，一种调节性抗体与 将对阿霉素进行评估。第三，使用有效的螯合系统 将放射性标记、本地化和有效性研究紧密结合在一起 比较与L6抗体螯合的伽马和贝塔发射体。到目前为止 L6抗体已经用放射性碘标记或 免疫组织学。最后，使用相同的螯合系统连接 L6抗体、顺磁性物质等放射性标记物 Gd，将被络合以结合MRI的空间分辨率 具有定位单抗的生物学特异性，如 作为L6。与这些研究相关的是神经毒性测试 具有非常不同解离的Gd造影剂 常量。 在这次竞争性更新中需要强调的第二个领域是 化疗药物联合用药的毒性和疗效 在没有渗透性血脑屏障紊乱之前，伴随着和之后 外放射治疗。毒性最小、最有效的两种 我们临床研究中的化疗组合 甲氨蝶呤和环磷酰胺以及最近的卡铂联合用药 和依托泊苷。这些组合的效果将在#年进行评估。 我们的裸鼠肿瘤模型采用LX-1人肺癌。在……里面 此外，由于过去成功地测试了三聚氰胺的神经毒性 化疗药物在动物体内的破坏作用 对于潜在的临床应用，我们将类似地研究几种新的药物。 疗效将不仅通过存活来评估，还将通过肿瘤体积来评估 在组织学和系列磁共振成像中评估反应的测量 活体扫描。神经毒性测试有了一个新的评估维度 我们测量动物脑电的能力。我们的总体目标是 继续改进抗肿瘤药物和显像剂的交付，以 脑肿瘤，最后评估治疗的疗效 接近了。这项提议是对#年宣布的计划的回应 外科肿瘤学，是外科CREG的延续。