HYPOXIA MODULATION OF PROTRACTED THERAPY

持久治疗的缺氧调节

• 批准号: 6584604
• 负责人: CAMERON J KOCH
• 金额: $ 29.41万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-05-01 至 2003-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6584604
• 关键词: cell cycle; cell line; human tissue; hypoxia; immunocytochemistry; neoplasm /cancer radiation therapy; neoplastic cell; oxygen consumption; radiation dosage; radiation therapy dosage; thiols; tissue /cell culture; xenotransplantation

Many factors lead to treatment-resistance in cancer therapy. Some factors physical-chemical in nature: examples are hypoxia or the presence of high thiol content, which increase radiation resistance by well-known chemical principles. Others have a biochemical and molecular- biological basis: examples are endogenous radio-resistance, cell-cycle blocks or modified repair. The interactions of these factors are poorly understood in vivo, and studies of basic mechanisms of treatment resistance must have a very broad base of investigation. Several studies have suggested that low dose-rate, protracted ration (LDRR) can provide significant therapeutic advantages over conventional fractioned therapy, which consists of multiple discrete dose administrations, each of which is at high dose-rate. In order to apply this information to the clinic, however, an understanding is required regarding the interaction of LDRR with the chemical and biological modifiers of radioresistance. It is becoming increasingly apparent that hypoxia plays a key role in determining radioresistance, not only in the countless rodent studies over several decades, but in the current management of human cancer therapy. This project will test for the interaction of hypoxia with the radiation response of cells to LDRR. Several key questions will be addressed; 1) is there a normal dependence of radiation resistance on oxygen partial pressure for low dose-rate radiotherapy? 2) does low oxygen partial pressure affect the cell-cycle redistribution caused by low dose-rate radiation? and 3) is the response after low dose-rate radiation in vivo mediated through changes in tissue hypoxia or thiol content? 4) are hypoxic tumor cells sensitized by IUdR? It is hoped that these investigations will allow a firm rationale for the use of LDRR in tumors containing hypoxic cells.

许多因素导致癌症治疗中的治疗耐药性。某些因素本质上是物理化学的：例子是缺氧或高硫醇含量的存在，这增加了众所周知的化学原理耐药性。其他的则具有生化和分子生物学基础：例子是内源性放射性，细胞周期块或修饰的修复。这些因素的相互作用在体内对待很少，并且对治疗抗性的基本机制的研究必须具有非常广泛的研究基础。几项研究表明，低剂量率，旷日持久期的口粮（LDRR）可以比常规分数疗法具有显着的治疗优势，该疗法由多种离散剂量施用组成，每种剂量都处于高剂量率。但是，为了将此信息应用于诊所，需要了解LDRR与放射线的化学和生物学修饰符的相互作用。越来越明显的是，缺氧在确定放射线方面起着关键作用，不仅在几十年来的无数啮齿动物研究中，而且在当前对人类癌症治疗的管理中。该项目将测试缺氧与细胞对LDRR的辐射反应的相互作用。将解决几个关键问题； 1）辐射抗性对低剂量速率放射疗法的氧气部分压力的正常依赖性吗？ 2）低氧部分压力是否会影响低剂量率辐射引起的细胞周期重新分布？ 3）在体内低剂量辐射辐射后的反应是通过组织缺氧或硫醇含量的变化而介导的？ 4）IUDR是否敏化低氧肿瘤细胞？希望这些研究将允许在含有低氧细胞的肿瘤中使用LDRR的牢固理由。