Adams G E
MRC Radiobiology Unit, Didcot, Oxfordshire, United Kingdom.
Radiat Res. 1992 Nov;132(2):129-39.
A brief review is presented of the background to, and the principles involved in, the development of redox-sensitive drugs for use in cancer therapy. The role of redox processes in the action of various types of radiosensitizers and in the activation of bioreductive drugs is described. The mechanisms by which many simple hypoxic cell radiosensitizers act are believed to involve fast electron transfer processes involving DNA. Some of these agents can also function as hypoxic cell cytotoxins, although the mechanisms involved are different. These "bioreductive drugs" are activated by intracellular metabolic reduction mediated through various cellular reductases. Usually, though not always, bioreduction is favored under hypoxic conditions, and this is why many of these compounds display differential cytotoxicity to hypoxic cells. This is one of the rationales for selectivity in solid tumors. The potencies of both hypoxic cell radiosensitizers and bioreductive drugs are strongly correlated with their electron affinities. Classes of bioreductive agents of current interest are described briefly. These include simple and dual-function nitroheterocycles including the highly potent compound RB-6145, quinone-based drugs including analogues of mitomycin C, and heterocyclic compounds containing N-oxide functions. The study of bioreductive agents for potential use as adjuncts for various approaches to cancer treatment is described.
本文简要回顾了用于癌症治疗的氧化还原敏感药物的研发背景及相关原理。描述了氧化还原过程在各类放射增敏剂作用以及生物还原药物激活中的作用。许多简单的乏氧细胞放射增敏剂的作用机制被认为涉及与DNA相关的快速电子转移过程。其中一些药物也可作为乏氧细胞细胞毒素发挥作用，尽管其作用机制有所不同。这些“生物还原药物”通过各种细胞还原酶介导的细胞内代谢还原而被激活。通常（但并非总是如此），生物还原在乏氧条件下更易发生，这就是为什么许多此类化合物对乏氧细胞表现出不同的细胞毒性。这是实体瘤选择性的理论依据之一。乏氧细胞放射增敏剂和生物还原药物的效力都与其电子亲和力密切相关。简要介绍了当前备受关注的几类生物还原药物。这些包括简单和双功能的硝基杂环化合物（包括高效化合物RB - 6145）、基于醌的药物（包括丝裂霉素C的类似物）以及含有N - 氧化物功能的杂环化合物。阐述了对有望用作癌症治疗各种方法辅助药物的生物还原药物的研究。
