PERMEABILITY AND BLOOD FLOW IN BRAIN TUMORS

脑肿瘤的渗透性和血流

• 批准号: 3394967
• 负责人: DENNIS R GROOTHUIS
• 金额: $ 27.72万
• 依托单位: EVANSTON HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1975
• 资助国家: 美国
• 起止时间: 1975-05-01 至 1993-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3394967
• 关键词: Retroviridae; antineoplastics; autoradiography; avian sarcoma virus; brain neoplasms; cell differentiation; disease /disorder model; dogs; drug screening /evaluation; electron microscopy; glioma; histopathology; interference microscopy; laboratory rat; membrane permeability; microcirculation; neoplasm /cancer pharmacology; pharmacokinetics; radiotracer; retinoblastoma; viral carcinogenesis; virus cytopathogenic effect; virus related neoplasm /cancer

Malignant brain tumors are almost uniformly fatal. Brain tumor chemotherapy has been based on empiric principles rather than rational understanding of drug delivery processes, and has contributed little to improved quality or length of life in these patients. Our goal is to develop operational expressions to predict the amount of drug delivered to a brain tumor, and thus individualize chemotherapy for brain tumor patients. To do this, it is necessary to know properties of the drugs being used, and to measure certain physiological properties of the tumors being treated. Four Specific Aims will quantitatively study drug delivery parameters, and determine their effect on operational equations to predict tumor drug exposure. These Specific Aims are: 1) to determine if there is a linear relationship between the rate of transcapillary transport and the physicochemical properties of a drug, 2) to determine whether a similar relationship exists between drug properties and transmembrane transport into brain tumor cells, 3) to determine if diffusion, either within a tumor or in brain around tumor, limits tumor cell drug exposure, and, 4) to determine if commonly used treatment modalities for brain tumors (e.g., dexamethasone or radiation) affect drug delivery parameters. Since delivery of both lipid and water-soluble drugs is limited in many individual brain tumors, Specific Aim 5 seeks to explore ways of selectively increasing tumor drug delivery. Specific Aim 6 seeks to develop operational expressions to express the formation of tumor-associated brain edema, and determine how treatment of this edema affects drug delivery processes. These studies utilize well established rat and dog brain tumor models in vivo, and rat and human glioma cell lines in vitro. We will use three experimental methodologies to obtain quantitative measurements of drug concentration: quantitative autoradiography (QAR), high performance liquid chromatography (HPLC), and computed tomographic (CT) techniques that were developed in our laboratory at Evanston Hospital.

恶性脑肿瘤几乎都是致命的。 脑肿瘤 化疗是基于经验性原则而不是理性的 药物输送过程的理解，并没有做出贡献， 改善这些患者的生活质量或寿命。 我们的目标是 开发操作表达式来预测药物递送到 脑肿瘤，从而使脑肿瘤的化疗个性化 患者 要做到这一点，有必要了解药物的性质 并测量肿瘤的某些生理特性 接受治疗 四个具体目标将定量研究药物递送 参数，并确定它们对要预测的运算方程的影响 肿瘤药物暴露。 这些具体目标是：1）确定是否存在 跨毛细血管转运速率与 药物的理化性质，2）以确定是否类似 药物性质与跨膜转运之间存在关系 进入脑肿瘤细胞，3）以确定是否扩散，无论是在肿瘤内 或在肿瘤周围的脑中，限制肿瘤细胞药物暴露，以及，4） 确定脑肿瘤的常用治疗方式（例如， 地塞米松或放射）影响药物递送参数。 以来 脂质和水溶性药物的递送在许多情况下是有限的 个别脑肿瘤，具体目标5寻求探索的方法， 选择性地增加肿瘤药物递送。 具体目标6旨在 发展运算表达式来表示 肿瘤相关性脑水肿，并确定如何治疗这种水肿 影响药物输送过程。 这些研究利用了公认的 体内大鼠和狗脑肿瘤模型以及大鼠和人胶质瘤细胞系 体外 我们将使用三种实验方法来获得 药物浓度的定量测量：定量 放射自显影（QAR）、高效液相色谱（HPLC）和 计算机断层扫描（CT）技术是在我们的实验室开发的 在埃文斯顿医院