HYPOXIA MODULATION OF PROTRACTED THERAPY

许多因素导致癌症治疗中的治疗抵抗。一些因素是物理化学性质的：例如缺氧或存在高硫醇含量，这通过众所周知的化学原理增加了耐辐射性。其他的则有生物化学和分子生物学基础：例如内源性辐射抗性、细胞周期阻滞或修饰修复。这些因素的相互作用在体内了解甚少，治疗耐药的基本机制的研究必须有一个非常广泛的调查基础。几项研究表明，低剂量率，延长配给（LDRR）可以提供显着的治疗优势，传统的分次治疗，其中包括多个离散剂量的管理，其中每一个是在高剂量率。然而，为了将这些信息应用于临床，需要了解LDRR与辐射抗性的化学和生物修饰剂的相互作用。越来越明显的是，缺氧在决定放射抗性方面起着关键作用，不仅在过去几十年的无数啮齿动物研究中，而且在目前的人类癌症治疗管理中。该项目将测试缺氧与细胞对LDRR的辐射反应的相互作用。几个关键问题将得到解决：1）是否有一个正常的依赖性，辐射阻力的氧分压低剂量率放射治疗？2)低氧分压是否影响低剂量率辐射引起的细胞周期再分配？以及3）低剂量率辐射后的体内反应是否通过组织缺氧或巯基含量的变化介导？4)缺氧肿瘤细胞是否被IUdR致敏？希望这些研究将为在含有缺氧细胞的肿瘤中使用LDRR提供坚实的理论基础。

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.