Nicoletto Rachel E, Ofner Clyde M
Department of Pharmaceutical Sciences, Philadelphia College of Pharmacy, University of the Sciences in Philadelphia, 600 South 43rd Street, Philadelphia, PA, 19101-4495, USA.
Cancer Chemother Pharmacol. 2022 Mar;89(3):285-311. doi: 10.1007/s00280-022-04400-y. Epub 2022 Feb 12.
Doxorubicin (DOX) is a chemotherapeutic agent frequently used for the treatment of a variety of tumor types, such as breast cancer. Despite the long history of DOX, the mechanistic details of its cytotoxic action remain controversial. Rather than one key mechanism of cytotoxic action, DOX is characterized by multiple mechanisms, such as (1) DNA intercalation and adduct formation, (2) topoisomerase II (TopII) poisoning, (3) the generation of free radicals and oxidative stress, and (4) membrane damage through altered sphingolipid metabolism. Many past reviews of DOX cytotoxicity are based on supraclinical concentrations, and several have addressed the concentration dependence of these mechanisms. In addition, most reviews lack a focus on the time dependence of these processes. We aim to update the concentration and time-dependent trends of DOX mechanisms at representative clinical concentrations. Furthermore, attention is placed on DOX behavior in breast cancer cells due to the frequent use of DOX to treat this disease. This review provides insight into the mechanistic pathway(s) of DOX at levels found within patients and establishes the magnitude of effect for each mechanism.
阿霉素（DOX）是一种常用于治疗多种肿瘤类型（如乳腺癌）的化疗药物。尽管阿霉素应用历史悠久，但其细胞毒性作用的机制细节仍存在争议。阿霉素的细胞毒性作用并非由单一关键机制所致，而是具有多种机制，例如：（1）DNA嵌入和加合物形成；（2）拓扑异构酶II（TopII）中毒；（3）自由基生成和氧化应激；（4）通过改变鞘脂代谢造成膜损伤。过去许多关于阿霉素细胞毒性的综述是基于超临床浓度进行的，并且有几篇已经探讨了这些机制的浓度依赖性。此外，大多数综述缺乏对这些过程时间依赖性的关注。我们旨在更新在代表性临床浓度下阿霉素作用机制的浓度和时间依赖性趋势。此外，由于阿霉素常用于治疗乳腺癌，因此本文将重点关注其在乳腺癌细胞中的行为。本综述深入探讨了患者体内阿霉素作用机制的途径，并确定了每种机制的作用程度。
