Lown J W
Mol Cell Biochem. 1983;55(1):17-40. doi: 10.1007/BF00229240.
The review describes recent studies designed to elucidate the molecular mechanism of action of certain quinone antibiotics which exhibit or have potential for clinical treatment of malignant diseases. Although a large number of quinone antibiotics has been described the review will concentrate on four types, the anthracyclines, the mitomycins, streptonigrin, and the saframycin antibiotics because of their biological significance and because the understanding of their underlying modes of action is perhaps more advanced than in the case of other antibiotics. It will be evident that although the antibiotics bear a common quinone moiety this does not confer a commonality of mechanism. Indeed the variety and precision of the different chemical lesions induced by quinone antibiotics on nucleic acids, their principal cell targets, is remarkable. The particular lesions identified include (i) equilibrium binding, (ii) "permanent' single covalent attachment, (iii) reversible covalent binding, (iv) metal ion sequestration and subsequent DNA binding, (v) DNA groove and base specific binding, (v) interstrand cross-linking, (vi) intercalation with concomitant supercoil relaxation and duplex extension, (viii) redox cycling with production of reactive oxygen species and DNA single strand breaks, and (viii) single strand breaks as a result of phosphotriester formation. In many cases the chemical mechanisms involved in these individual processes may be elucidated in in vitro experiments on purified DNAs by the application of ethidium binding assays in conjunction with certain cellular repair enzymes and utilizing techniques including high field nuclear magnetic resonance and electron paramagnetic resonance spectroscopy. The data obtained in this way complement and extend information from cell culture and in vivo experiments. A coherent description of the multiple cellular effects of these reactive agents is emerging. Such reactions involve bioreductive activation of the quinone the subsequent course of which is precisely controlled by structural and stereochemical factors within the individual antibiotic. The concomitant chemical reactions on cellular macromolecules are beginning to be related to pharmacological properties including in the case of the anthracyclines, a plausible rationale for the molecular origin of the dose limiting cardiotoxicity.
这篇综述描述了近期旨在阐明某些醌类抗生素作用分子机制的研究，这些抗生素对恶性疾病具有临床治疗作用或有潜在治疗作用。尽管已描述了大量的醌类抗生素，但本综述将集中讨论四种类型，即蒽环类抗生素、丝裂霉素、链黑菌素和沙夫拉霉素类抗生素，这是因为它们具有生物学意义，而且与其他抗生素相比，对其潜在作用方式的了解可能更为深入。显而易见，尽管这些抗生素都含有一个共同的醌部分，但这并不意味着它们具有相同的作用机制。实际上，醌类抗生素在其主要细胞靶点核酸上诱导的不同化学损伤的多样性和精确性是显著的。已确定的特定损伤包括：（i）平衡结合；（ii）“永久性”单共价连接；（iii）可逆共价结合；（iv）金属离子螯合及随后的DNA结合；（v）DNA沟槽和碱基特异性结合；（v）链间交联；（vi）嵌入并伴随超螺旋松弛和双链延伸；（viii）氧化还原循环并产生活性氧和DNA单链断裂；以及（viii）由于磷酸三酯形成导致的单链断裂。在许多情况下，通过应用溴化乙锭结合试验并结合某些细胞修复酶，利用包括高场核磁共振和电子顺磁共振光谱在内的技术，在纯化DNA的体外实验中可以阐明这些单个过程所涉及的化学机制。以这种方式获得的数据补充并扩展了来自细胞培养和体内实验的信息。对这些反应性药物多种细胞效应的连贯描述正在形成。此类反应涉及醌的生物还原活化，其后续过程由各个抗生素内的结构和立体化学因素精确控制。细胞大分子上伴随的化学反应开始与药理学特性相关，例如在蒽环类抗生素的情况下，为剂量限制性心脏毒性的分子起源提供了一个合理的解释。
