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

前列腺癌热疗的分子反应——热休克反应

• 批准号: 6236640
• 负责人: STUART Keith CALDERWOOD
• 金额: $ 32.79万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-06-01 至 1998-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6236640
• 关键词: adenocarcinoma; antiinflammatory agents; biological signal transduction; biopsy; combination cancer therapy; drug design /synthesis /production; enzyme inhibitors; gene expression; human therapy evaluation; hyperthermia therapy; imidazole; immunocytochemistry; mitogen activated protein kinase; molecular oncology; neoplasm /cancer chemotherapy; neoplasm /cancer thermotherapy; neoplastic cell; prostate neoplasms; radiation sensitivity; radiosensitizer; stress proteins; tissue /cell culture

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.

我们的目的是研究热疗在腺癌治疗中的作用 并将探讨细胞和分子因素， 控制前列腺癌对高温和辐射的反应， 目的是优化治疗 很明显， 通过热疗治疗肿瘤的有效性由热控制， 休克反应，一种复杂的细胞反应，涉及协调的 一组编码热休克蛋白（HSP）的基因的表达， 保护细胞蛋白在热休克，激活的压力 激酶和促炎脂质调节剂的释放， 介导对治疗的耐药性。 我们的目标是将这些知识应用于前列腺癌，作为研究的基础。 设计合理的治疗方案，通过两大途径。 首先，我们的目标是 开发不用于癌症主要治疗的药物的使用， 相对无毒的高温致敏。 我们将研究三个案例 药物包括：（i）硝基咪唑缺氧细胞敏化剂， （ii）非甾体抗炎药（NSAID）和 (iii)蛋白激酶抑制剂。 这些药物的靶点是 细胞内的高热（热休克反应; iii）和组织 热反应（微循环和炎症变化; i，ii）。 的 优化热疗的第二个主要方法是监测 诱导热休克反应的患者活检前， 作为肿瘤敏感性的测定。 我们 将测量HSP 70的肿瘤浓度，HSP 70的表达 与细胞对高温的抵抗力密切相关。这 将使我们能够确定的反应之间的关系， 前列腺癌患者辅助热疗和激活 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 通过开发对高温耐受的肿瘤的测定法 可以用热疗过程中产生的热疗增敏剂治疗， 项目