DNA as a target of alkylating carcinogens.
DNA as a target of alkylating carcinogens.
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DNA 作为烷基化致癌物的靶标。
DOI：
10.1093/oxfordjournals.bmb.a071608
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发表时间：
1980
影响因子：
6.7
通讯作者：
P. D. Lawley
中科院分区：
文献类型：
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作者：
P. D. Lawley
英国医学公报（Brookes & Lawley，1964）中关于烷化剂致癌作用的既往综述的结论是，尽管这些试剂是体内反应与致癌作用之间相关性的合适选择，但尚未定义关键反应。原因是潜在的细胞靶点，包括蛋白质、RNA和DNA，都被烷基化到大约相同的程度，以每单位重量材料的烷基化表示。证据的平衡可能导致考虑DNA作为关键目标，因为癌症的体细胞突变理论由来已久，例如Strong（1949）的评论，相关文献可追溯到1890年。自1964年以来，这一理论显然得到了相当大的加强，因为观察到所有类别的化学致癌物（如二烷基亚硝胺、多环芳烃、氯乙烯、黄曲霉毒素）的代表都可以被证明是诱变剂（见Venitt，1980），在许多情况下通过代谢活化产生烷化剂。这项工作的主要重点是定性的，诱变试验的阳性结果提供了一个敏感的指标，是否致癌物或其代谢产物可以与DNA反应。最近，注意力已被定向到DNA反应在体内和致癌作用之间的定量相关性，不仅相对于反应的整体程度，而且具体的反应。具有简单化学结构的烷基化剂不需要代谢活化就能与DNA发生反应，这在这些研究中证明是有价值的，因为它们显示出与致瘤作用相关的适当化学反应谱（见表I）。作为这种相关性的主要决定因素出现的反应是在DNA中鸟嘌呤的0-6原子处的烷基化，由Loveless（1969）提出。这加强了沃森-克里克方案中烷基化鸟嘌呤与胸腺嘧啶碱基配对的错误编码（参见图1），从而解释了在烷化剂诱变中观察到的GC-> AT转换突变的优势（Krieg，1963; Coulondre和米勒，1977）。利用T2噬菌体的胞外烷基化比较研究一系列烷基化剂的致突变性和化学反应性（Loveless和汉普顿，1969年）支持这样的概念：突变可以通过O 6-烷基鸟嘌呤的错误编码来诱导（图la），但不是通过之前针对7-烷基鸟嘌呤的离子化形式提出的类似错误配对（图lc）（Lawley和Brookes，1961年）。
The conclusion of the previous review of carcinogenesis by alkylating agents in British Medical Bulletin (Brookes & Lawley, 1964) was that, although these agents were a suitable choice for correlations between in-vivo reactions and carcinogenic action, the critical reactions had not been defined. The reason was that potential cellular targets, including proteins, RNA and DNA, were all alkylated to about the same extent, expressed as alkylations per unit weight of material. The balance of the evidence could lead to consideration of DNA as the critical target, because of the long-standing somatic cell mutation theory of cancer, as reviewed for example by Strong (1949), with a relevant literature going back to 1890. Since 1964, this theory has apparently been considerably strengthened by observations that representatives of all classes of chemical carcinogen (eg dialkylnitrosamines, polycyclic aromatic hydrocarbons, vinyl chloride, aflatoxins) can be shown to be mutagens (see Venitt, 1980), in many cases through metabolic activation to yield alkylating agents. The main emphasis in this work has been qualitative, and positive results in mutagenesis tests have provided a sensitive index of whether carcinogens or their metabolites can react with DNA. More recently, attention has been directed towards quantitative correlations between DNA reactions in vivo and carcinogenesis, not only with respect to the over-all extent of reaction but also to specific reactions. Alkylating agents of simple chemical structure that do not require metabolic activation to enable their reaction with DNA to take place have proved valuable in these studies, since they show a suitable spectrum of chemical reactivity correlating with tumorigenic action (see Table I).The reaction which has emerged as a main determinant of this correlation is alkylation at the 0-6 atom of guanine in DNA, as proposed by Loveless (1969). This potentiates mis-coding in the Watson-Crick scheme for base-pairing of alkylated guanine with thy mine (see fig. 1), thus accounting for the observed predominance of GC-» AT transition mutations in mutagenesis by alkylating agents (Krieg, 1963; Coulondre & Miller, 1977). A comparative study of mutagenicity and chemical reactivity of a series of alkylating agents, using extracellular alkylation of T2 bacteriophage (Loveless & Hampton, 1969), supported the concept that mutation could be induced by mis-coding of O6-alkylguanine (fig. la), but not by the analogous mis-pairing previously suggested for the ionized form of 7-alkylguanine (fig. lc)(Lawley & Brookes, 1961).