PERMEABILITY AND BLOOD FLOW IN BRAIN TUMORS

恶性脑瘤几乎都是致命的。脑瘤 化疗一直是基于经验原则，而不是理性的 对药物输送过程的了解，对 改善了这些患者的生活质量或生存时间。我们的目标是 开发运算式以预测药物输送到 脑瘤，因此脑瘤的个体化化疗 病人。要做到这一点，有必要了解药物的性质 用于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输送 参数，并确定它们对运算方程的影响以进行预测 肿瘤药物暴露。这些具体目标是：1)确定是否有 跨毛细管转运速率与血流量之间的线性关系 药物的物理化学性质，2)确定类似的 药物性质与跨膜转运之间存在关系 进入脑瘤细胞，3)以确定扩散，无论是在肿瘤内 或在肿瘤周围的脑中，限制肿瘤细胞药物的暴露，以及，4) 确定脑瘤的常用治疗方式(例如， 地塞米松或辐射)影响药物传递参数。自.以来 脂类药物和水溶性药物在许多方面都受到限制 个别脑瘤，特定目标5寻求探索治疗方法 有选择地增加肿瘤药物的输送。具体目标6旨在 开发运算表达式，以表达形成 与肿瘤相关的脑水肿，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 大鼠和犬体内脑肿瘤模型及大鼠和人脑胶质瘤细胞系 在试管中。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 我们实验室开发的计算机断层扫描(CT)技术 在埃文斯顿医院。

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.