PREFERENTIAL KILLING OF MELANIZED TISSUES

优先杀死黑色化组织

• 批准号: 2091514
• 负责人: PETER M. CORRY
• 金额: $ 28.84万
• 依托单位: WILLIAM BEAUMONT HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-09-01 至 1997-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2091514
• 关键词: central nervous system neoplasms; combination cancer therapy; cytolysis; gel electrophoresis; head /neck neoplasm; human subject; melanoma; neoplasm /cancer thermotherapy; stress proteins; thorax neoplasm

The overall objective of this research program is the development of hyperthermia for the treatment of human cancer. At the present time the ability to controllably elevate local tumor temperatures is a major impediment in clinical applications. Here we present approaches toward improved clinical systems. To better understand how such systems should be applied in the future, basic biological investigations into the mechanisms associated with heat killing and potentiation of other anticancer treatments are also put forward. Proposed is the development of a processing field magnetic induction system for the treatment of bulky deep seated human neoplasms including intrathoracic tumors. This system offers a number of significant advantages over existing systems as well as a number of drawbacks, particularly unwanted power deposition in normal tissues surrounding tumors. The development of this system is a test of the hypothesis that processing magnetic fields can be exploited to substantially improve hyperthermia for large and deep seated tumors. This will be accomplished by reducing the presently limiting toxicities associated with unwanted power deposition in normal issues and improving the specific absorption rate (SAR) in tumors. Interstitial radiation therapy, brachytherapy, is the treatment of choice for a variety of human neoplasms and is ideally suited to combination with hyperthermia. In addition data presented in the progress report section demonstrated a cohort of difficult to heat, probably highly perfused, human tumors. To address this area, we propose the development of An "N" electrode interstitial hyperthermia system for tumors in the head and neck, thorax, pelvis/perineum, and central nervous system. To advance our understanding of how best to apply hyperthermia to the cancer problem, we also propose biological investigations to elucidate the mechanism of hyperthermic cell killing, protection from and sensitization to heat insult and the potentiation of other agents, e.g ionizing radiation and chemotherapeutic drugs. Central to this line of investigation is the hypothesis that protein influx to the nucleus after heat insult is primarily a cytotoxic rather than cytoprotective event. We believe that this increase in nuclear affinic proteins (NAP) becomes cytotoxic by inhibiting, among other things, DNA transcription and replication and by the suppression of repair of damage caused by other agents. A comprehensive model is presented in an attempt to unify a large body of literature dealing with thermal biology. It centers around cytoplasmic release of the NAP under stress (e.g. heat) and the specific binding of these proteins to nuclear matrix binding sites (NMBS). After the stress or threat to the cell is removed the heat stress proteins (HSP) then remove the NAP and resequester them in cytoplasm. While the model is imperfect it offers explanations for such diverse phenomena as thermal tolerance (TT) and heat potentiation of radiation and drugs and we have used it to develop a comprehensive laboratory test of the hypothesis.

该研究计划的总体目标是发展 高温治疗人类癌症的治疗。 目前 时间可以控制升高局部肿瘤温度的能力 是临床应用中的主要障碍。 我们在这里介绍 改善临床系统的方法。 更好地理解 将来应如何应用此类系统，基本生物学 调查与杀热和杀热有关的机制 还提出了其他抗癌治疗的增强。 提出的是处理场磁的发展 用于治疗笨重的深座的诱导系统 肿瘤包括胸腔肿瘤。 该系统提供了 与现有系统以及 许多缺点，尤其是不需要的功率沉积 肿瘤周围的正常组织。 该系统的发展 是对处理磁场可以是的假设的检验 被利用以实质上改善大和深度的热疗 座位的肿瘤。 这将通过减少目前的减少来实现 限制与不需要功率沉积有关的毒性 正常问题并提高特定的吸收率（SAR） 肿瘤。 间质性放射疗法，近距离放射治疗是 选择各种人类肿瘤的选择，理想情况下是 适合与热疗结合。 另外数据 在“进度报告”部分中介绍了一群 很难加热，可能是高度灌注的人类肿瘤。 到 解决该区域，我们提出了“ N”电极的开发 用于头部和颈部肿瘤的间质高温系统， 胸腔，骨盆/阴部和中枢神经系统。 为了促进我们对如何最好地将热疗应用于 癌症问题，我们还提出了生物学研究 阐明过度热细胞杀死的机制，保护 从敏感到热侮辱和其他 药物，例如电离辐射和化学治疗药物。 中央 对这一调查的方法是蛋白质流入的假设 热侮辱后对细胞核主要是一种细胞毒性 而不是细胞保护事件。 我们认为这增加了 核亲本蛋白（NAP）通过抑制，会变成细胞毒性 除其他外，DNA转录和复制以及 抑制其他药物造成的损害的修复。 一个 提出了综合模型，以统一大型模型 涉及热生物学的文献体系。 它以周围为中心 在压力下（例如热）和 这些蛋白质与核基质结合位点的特异性结合 （NMB）。 压力或对电池的压力或威胁后，热量 压力蛋白（HSP）然后去除小睡并将其重新安置 细胞质。 虽然模型不完美，但它提供了解释 像热耐受性（TT）和热量等多样性现象 辐射和药物的增强，我们已经用它来发展 该假设的全面实验室检验。