MECHANISMS OF DRUG-INDUCED HEAT PROTECTION

热疗的临床应用已取得长足进展 在过去的十年里。 这种方式，其中肿瘤被加热， 42摄氏度至47摄氏度的温度，已被证明是 与放射治疗结合时有益，或 化疗 在低温疗法可以应用于大多数 有效地，一个基本的了解如何热杀死细胞， 需要设置 尽管有大量的研究和丰富的理论， 高温致死的机制仍然没有很好的理解。 这项研究的目的是阐明细胞的 以及热杀死的分子机制， 某些化合物保护细胞免受热诱导 损害 特别感兴趣的是两种化合物， 放线菌酮和嘌呤霉素，它们已知抑制蛋白质 合成并提供细胞热保护。 由于抑制 蛋白质合成本身并不一定提供 保护，其他几个生化过程将 研究以确定它们在热稳定中的作用。 这些研究将首先包括确定 药物修饰的蛋白质降解速率与 药物改变的热敏感性 其次，泛素的作用， 多胺对放线菌酮或嘌呤霉素的热保护作用将 追究 稳定效果的测定 化学试剂对分离的酶如eIF-4F和 细胞内环境也是拟议研究的一部分。 实验将在受控环境中生长的细胞上进行。 培养条件和分离的亚细胞系统。 这些 研究将提供更好的了解机制， 高温杀死细胞，希望能让我们 提高临床热疗的疗效。

Clinical application of hyperthermia has progressed considerably in the past decade. This modality, in which tumors are heated to tempatures of 42 degrees C to 47 degrees C, has been shown to be beneficial when combined with radiation therapy or chemotherapy. Before hypoerthermia can be applied most effectively, a fundamental understanding of how heat kills cells will be needed. Despite much research and abundant theories, the mechanisms of hyperthermic killing are still not well understood. The objective of the proposed study is to elucidate the cellular and molecular mechanisms of heat killing and determine how certain chemical compounds protect cells from heat-induced damage. Of particular interest are two compounds, cycloheximide and puromycin, which are known to inhibit protein synthesis and afford cellular heat protection. Since inhibition of protein synthesis in and of itself does not necessarily provide protection, several other biochemical processes will be investigated to determine their role in thermal stabilization. These studies will consist firstly of the determination of the relationships between drug-modified protein degradation rate and drug-altered heat sensitivity. Secondly the role of ubiquitin and polyamines on heat protection by cycloheximide or puromycin will be investigated. The determination of stabilizing effects of chemical agents on isolated enzymes such as eIF-4F and intracellular environment is also part of the proposed research. Experimentation will be performed on cells growing in controlled culture conditions and on isolated subcellular systems. These studies will provide a better understanding of mechanisms of hyperthermic killing of cells and hopefully will enable us to improve the efficacy of clinical hyperthermia.