Doxorubicin pathways: pharmacodynamics and adverse effects.
Doxorubicin pathways: pharmacodynamics and adverse effects.
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DOI：
10.1097/fpc.0b013e32833ffb56
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发表时间：
2011-07
影响因子：
2.6
通讯作者：
Altman RB
中科院分区：
文献类型：
--
作者：
Thorn CF;Oshiro C;Marsh S;Hernandez-Boussard T;McLeod H;Klein TE;Altman RB
本研究的目的是简要介绍支持多柔比星作用的PharmGKB途径的文献背景，并对这一活跃的研究领域进行总结。读者可以参考最近的深度综述[1-4]，以获得关于这一重要而复杂途径的更详细讨论。阿霉素是一种蒽蒽类药物，最早于20世纪70年代从peucetius变种caesius链霉菌中提取，常规用于治疗乳腺癌、肺癌、胃癌、卵巢癌、甲状腺癌、非霍奇金淋巴瘤和霍奇金淋巴瘤、多发性骨髓瘤、肉瘤和儿童癌症等多种癌症[5-7]。阿霉素使用的一个主要限制是心脏毒性，目前用于预测毒性的唯一标准是总累积剂量[4,8]。由于有证据表明，抗癌作用和心脏毒性的机制是通过不同的途径发生的，因此有希望开发出具有同等疗效但毒性较低的蒽环类药物。对这些途径的药物基因组学知识可能最终允许将来选择更有可能在较低剂量下获得疗效或能够承受较低毒性的较高剂量的患者。我们在这里展示了阿霉素在程定化癌细胞中的药物基因组学作用（图1）和心肌细胞毒性（图2）的候选基因的图形表示，以及描述迄今为止检查的关键变体的表格。
The goal of this study is to give a brief background on the literature supporting the PharmGKB pathway about doxorubicin action, and provides a summary of this active area of research. The reader is referred to recent in-depth reviews [1–4] for more detailed discussion of this important and complex pathway. Doxorubicin is an anthracyline drug first extracted from Streptomyces peucetius var. caesius in the 1970’s and routinely used in the treatment of several cancers including breast, lung, gastric, ovarian, thyroid, non-Hodgkin’s and Hodgkin’s lymphoma, multiple myeloma, sarcoma, and pediatric cancers [5–7]. A major limitation for the use of doxorubicin is cardiotoxicity, with the total cumulative dose being the only criteria currently used to predict the toxicity [4, 8]. As there is evidence that the mechanisms of anticancer action and of cardiotoxicity occur through different pathways there is hope for the development of anthracycline drugs with equal efficacy but reduced toxicity [4]. Knowledge of the pharmacogenomics of these pathways may eventually allow for future selection of patients more likely to achieve efficacy at lower doses or able to withstand higher doses with lesser toxicity. We present here graphical representations of the candidate genes for the pharmacogenomics of doxorubicin action in a stylized cancer cell (Fig. 1) and toxicity in cardiomyocytes (Fig. 2), and a table describing the key variants examined so far.