Newer approaches to the study of the mechanisms of action of antitumor antibiotics
Newer approaches to the study of the mechanisms of action of antitumor antibiotics
复制标题
研究抗肿瘤抗生素作用机制的新方法
DOI：
10.1021/ar00084a001
复制
发表时间：
1982
影响因子：
18.3
通讯作者：
J. Lown
中科院分区：
文献类型：
--
作者：
J. Lown
大自然在抗生素的设计和生物合成方面表现出非凡的独创性(图1)。虽然抗菌素已经引起了人们的极大兴趣，但人们可以用化学术语以任何程度的信心为其制定作用机制的1/2很少。2我想在本报告中讨论的特定领域涉及抗肿瘤抗生素的作用机制。尽管确定抗生素作用的机制是一个化学问题，但它显然需要多学科的方法。大量的体内和体外药理学证据，包括病毒的灭活和抗分裂、诱变和细胞学效应，表明DNA是许多抗肿瘤抗生素的关键细胞靶点，因为它的细胞功能对化学变化敏感。2这类药物可通过直接抑制复制酶或通过与核酸模板的各种相互作用，在核苷酸代谢水平上抑制核酸的细胞功能。2 DNA是一个有吸引力的研究药物靶点，因为它或多或少具有明确的几何结构。2·3研究具有核酸功能的抗生素抑制剂时需要的特定信息类型分为三类：1.抗生素。(1)药物是否与复制酶或蛋白质、DNA聚合酶、RNA聚合酶、旋转酶、拓扑异构酶、螺旋不稳定蛋白反应，或直接与核酸模板反应？(Ii)药物是否需要特殊的激活、还原、氧化或质子化，如果需要，在哪里？(Iii)它是否需要辅助因子，如金属离子或
Nature displays extraordinary ingenuity in the design and biosynthesis of antibiotics (Figure 1). While an-tibiotics have attracted a great deal of interest, 1· 2 those for which one may formulate a mechanism of action in chemical terms with any degree of confidence are few in number. 2 The particular area I wish to address in this Account concerns the mechanism of action of an-titumor antibiotics. Although determining the mechanism of antibiotic action is a chemical problem, it clearly requires a multidisciplinary approach. Considerable pharmacological evidence both in vivo and in vitro, including the inactivation of viruses and antimitotic, mutagenic, and cytological effects, indicates that DNA is a critical cell target for many antitumor antibiotics owing to the sensitivity of its cellular func-tion to chemical alteration. 2 Such drugs may inhibit the cellular functions of nucleic acids at the level of nucleotide metabolism, by direct inhibition of replica-tive enzymes or by interactions of various kinds with nucleic acid templates. 2 DNA is an attractive drug target for study since it has, more or less, a defined geometry. 2· 3The types of specific information one requires when investigating an antibiotic inhibitor of nucleic acid functions fall into three categories: 1. The Antibiotic.(i) Does the drug react with a replicative enzyme or protein, DNA polymerase, RNA polymerase, gyrase, topoisomerase, helix destabilizing protein or directly with the nucleic acid template?(ii) Does the drug require specific activation, reduc-tion, oxidation, or protonation, and if so where?(iii) Does it require a cofactor such as metal ions or