MOLECULAR RESPONSE TO HYPERTHERMIA IN PROSTATE CARCINOMA--HEAT SHOCK RESPONSE

本研究旨在探讨热疗在腺癌治疗中的作用。 并将探索细胞和分子因素 控制前列腺癌对高温和辐射的反应， 以优化治疗为目的。现在已经很明显了， 热疗治疗肿瘤的疗效取决于热度 休克反应，一种复杂的细胞反应，涉及协调 编码热休克蛋白(HSPs)的一组基因的表达 在热休克、应激激活过程中保护细胞蛋白质 激酶和促炎性脂质调节剂的释放可能 调解对治疗的抗药性。 我们的目标是将这一知识应用于前列腺癌，作为研究 合理设计治疗方案，通过两条主要途径。首先，我们的目标是 开发不用于癌症初级治疗的药物，如 相对无毒的高温会使人变得敏感。我们将审查三个案例 药物包括：(I)硝基咪唑缺氧细胞增敏剂和 生物还原药物(II)非类固醇抗炎药(NSAIDs) (Iii)蛋白激酶抑制剂。这些药物是针对反应的。 对细胞和组织内的高温(热休克反应；iii) 对热的反应(微循环和炎症变化；I、II)。这个 优化热疗的第二个主要途径是监测热疗的程度 在患者活检组织中诱导热休克反应之前和 治疗后用热疗作为肿瘤敏感性检测。我们 将测定肿瘤组织中热休克蛋白70的浓度，热休克蛋白的表达 与细胞对高温的抵抗力最为密切相关。这 将使我们能够确定以下反应之间的关系 前列腺癌与辅助性热疗及其激活的关系 热休克反应。 该项目的最终目标是通过以下方式加强肿瘤治疗 通过建立一种肿瘤耐高温试验进行热疗 可以用在治疗过程中产生的高温敏感剂来治疗 项目。

We aim to study the role of hyperthermia in the treatment of adenocarcinoma of the prostate and will explore the cellular and molecular factors that govern the response of prostate carcinoma to hyperthermia and radiation, with the aim of optimizing therapy. It has become clear that the effectiveness of tumor treatment by hyperthermia is governed by the heat shock response, a complex cellular responses which involves the coordinated expression of a cohort of genes encoding heat shock proteins (HSPs) that protect cellular proteins during heat shock, the activation of stress kinases and the release of pro-inflammatory lipid modulators that may mediate resistance to treatment. We aim to apply this knowledge to prostate carcinoma as a basis for the rational design of treatment, through two major routes. Firstly, we aim to develop the use of drugs not used for the primary treatment of cancer as relatively non-toxic hyperthermia sensitizes. We will examine three cases of drugs including; (i) nitroimidazole hypoxic cell sensitizes and bioreductive drugs (ii) non steroidal anti-inflammatory drugs (NSAIDs) and (iii) protein kinase inhibitors. The drugs ar targeted against responses to hyperthermia within the cell (heat shock response; iii) and tissue reactions to heat (microcirculatory and inflammatory changes; i, ii). The second major approach to optimizing hyperthermia is to monitor the degree of induction of the heat shock response in patient biopsies before and after treatment with hyperthermia as an assay for tumor sensitivity. We will measure the tumor concentration of HSP70, the HSP whose expression most closely correlates with the resistance of cells to hyperthermia. This will permit us to determine the relationship between the responses of prostate carcinomata to adjuvant hyperthermia and the activation of the heat shock response. The ultimate aim of the project is to enhance tumor treatment by hyperthermia by developing an assay for tumors resistant to hyperthermia that can be treated with the hyperthermia sensitizes developed during the project.