HYPOXIA MODULATION OF PROTRACTED THERAPY

在癌症治疗中，导致治疗耐药的因素很多。自然界中的一些物理化学因素：例如低氧或高硫醇含量的存在，这些因素通过众所周知的化学原理增加了抗辐射能力。其他的则有生化和分子生物学基础：例如内源性放射抗性、细胞周期阻断或修饰修复。这些因素的相互作用在体内了解得很少，对治疗耐药的基本机制的研究必须有非常广泛的调查基础。一些研究表明，与传统的分次给药相比，低剂量率延长比(LDRR)具有显著的治疗优势，传统的分次给药由多个离散剂量给药组成，每个剂量都处于高剂量率。然而，为了将这一信息应用于临床，需要了解LDRR与辐射抗性的化学和生物调节剂之间的相互作用。越来越明显的是，缺氧在确定辐射抗性方面发挥着关键作用，不仅在几十年来无数的啮齿动物研究中，而且在目前的人类癌症治疗管理中。该项目将测试低氧与细胞对LDRR的辐射反应的相互作用。将解决几个关键问题：1)低剂量率放射治疗的辐射抵抗与氧分压之间是否存在正常的依赖关系？2)低氧分压是否影响低剂量率辐射引起的细胞周期重分布？3)体内低剂量率照射后的反应是否通过组织缺氧或硫醇含量的变化来介导？4)低氧肿瘤细胞是否对IUdR？希望这些研究将为LDRR在含有低氧细胞的肿瘤中的使用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.