HYPOXIA MODULATION OF PROTRACTED THERAPY

许多因素导致癌症治疗中的耐药。自然界中的一些物理化学因素：例如缺氧或高硫醇含量的存在，根据众所周知的化学原理，它们会增加抗辐射性。其他有生物化学和分子生物学基础：例如内源性无线电抗性，细胞周期阻滞或修饰修复。这些因素在体内的相互作用知之甚少，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。几项研究表明，低剂量率长期定量（LDRR）比传统的分次治疗具有显著的治疗优势，后者由多次离散剂量给药组成，每次都是高剂量率。然而，为了将这些信息应用于临床，需要了解LDRR与放射性耐药的化学和生物修饰剂的相互作用。越来越明显的是，缺氧在决定放射抵抗中起着关键作用，不仅在几十年来无数的啮齿动物研究中如此，而且在目前的人类癌症治疗管理中也是如此。这个项目将测试缺氧与细胞对LDRR的辐射反应的相互作用。将讨论几个关键问题；1)低剂量率放射治疗的放射抵抗是否正常依赖于氧分压？2)低氧分压是否影响低剂量率辐射引起的细胞周期再分布？3)体内低剂量率辐射后的反应是否通过组织缺氧或硫醇含量的变化介导？4)低氧肿瘤细胞是否对IUdR敏感？希望这些研究将为在含有缺氧细胞的肿瘤中使用LDRR提供一个坚实的理论基础。

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.