MEMBRANE COMPOSITION AND HYPERTHERMIC CELL DEATH

这些研究基于这样的假设：细胞膜， 特别是膜脂的组织完整性，是 热疗的初始目标。 这些研究的持续目标是 描述膜后的直接或间接响应 导致细胞死亡的损伤，以区分机制 负责热和辐射杀灭并制定协议 增强热敏感性。 假设的一项检验是检验 在修改方案下生长的细胞和组织的热敏感性 以系统的方式分析其膜的脂质成分。 的 一系列生物体的热和辐射敏感性进展 从大肠杆菌的脂肪酸营养缺陷型 K1060 到生物复杂性 体内实体瘤，CA755乳腺癌移植到 BDF1，小鼠将被研究。 一种改变脂肪酸的方案 L1060系统的介质补充发挥近乎绝对的控制 细胞的生化组成和生物物理特征 膜。 另一种方案利用膳食亚油酸酯的变化 启动实体瘤模型的适应性反应，这往往会 维持宿主组织膜和较小程度的肿瘤膜 最佳功能的属性。 在这个系统中有一些协议（例如， 局部和全身麻醉剂、胆固醇抑制剂）会干扰 饮食介导的膜组成适应性反应。 坠落 在生物复杂性的这些极端之间有两个模型：大肠杆菌 B/r 和 Bs-1 以及 V79 和 P388 哺乳动物细胞。 每个协议包括 膜成分的详尽分析（磷脂种类， 相对比例、浓度和脂肪酸模式；蛋白质 浓度和二维 PAGE 模式，并在适当时 胆固醇浓度、脂多糖浓度、脂肪酸 模式和微粘度），其结果将在 与生物体热敏感性变化的关系。 这些型号 提供了一种比较高热诱导机制的方法 膜引发的细胞杀伤和辐射杀伤。 这些研究 适应性耐热性和高温致死性的目的是 回答与临床研究设计相关的问题 高热。

These studies are predicated on the hypothesis that the cellular membrane, specifically the organizational integrity of the membrane lipids, is the initial target of hyperthermia. The continuing goals of these studies are to delineate the direct or indirect response subsequent to the membrane insult which leads to cell death, to differentiate the mechanisms responsible for heat and irradiation killing and to develop protocols which enhance thermosensitivity. One test of the hypothesis is to examine the thermosensitivity of cells and tissues grown under protocols which modify in a systematic manner the lipid constituents of their membranes. The thermal and irradiation sensitivities of a series of organisms progressing in biological complexity from a fatty acid auxotroph of E. coli, K1060 to an in vivo solid tumor, the CA755 mammary adenocarcinoma transplanted to a BDF1, mouse will be studied. One protocol which varies the fatty acid supplement of the medium for the L1060 system exerts near absolute control on the biochemical make up and biophysical characteristics of the cell membrane. Another protocol utilizes variation in dietary linoleate initiate adaptive responses for the solid tumor model which tend to maintain host tissue membrane and to a lesser extent tumor membrane properties for optimal function. In this system there are protocols (e.g., local and systemic anesthetics, cholesterol inhibitors) which interfere with the diet-mediated adaptive responses in membrane composition. Falling between these extremes in biological complexity are two models, the E. coli B/r and Bs-1 and V79 and P388 mammalian cells. Each protocol includes the exhaustive analysis of membrane constitutents (phospholipid species, relative proportion, concentrations, and fatty acid patterns; protein concentration and two dimensional PAGE patterns, and when appropriate cholesterol concentration, lipopolysaccharide concentration, fatty acid pattern and microviscosity), the results of which will be examined in relation to shifts in the organisms thermal sensitivity. These models provide a means for comparing the mechanisms of hyperthermia-induced membrane-initiated cell killing and killing by irradiation. These studies of adaptive thermotolerance and hyperthermic lethality are intended to answer questions relevant to the design of clinical studies using hyperthermia.