顺铂耐药的分子机制

Molecular mechanisms of cisplatin resistance

顺铂被广泛用于多种类型的实体肿瘤的临床治疗.DNA是顺铂的主要靶点,顺铂结合会导致DNA损伤并诱发细胞凋亡.然而,顺铂化疗常常受到内在的和获得性的耐药性的限制.在过去30多年里,大量的研究致力于对顺铂耐药性的理解,并且提出了几种导致顺铂耐药性的分子机制.这些机制显示顺铂的耐药性具有多因素特征.本文系统描述和讨论了顺铂的耐药性机制,包括细胞内药物积累的减少,药物去活作用的增强,DNA修复作用,DNA损伤反应和凋亡通路的变化以及一些间接信号通路的调控影响.

Cisplatin is widely used in the clinical treatment of many types of solid tumors. The cytotoxicity of cisplatin is primarily mediated by its binding to DNA followed by the DNA damage response and the induction of apoptosis. However, the cisplatin-based chemotherapy is often limited by the intrinsic or acquired drug resistance. During the past 30 years, intense researches have been conducted on the cisplatin resistance and the understanding about the molecular mechanisms has largely arisen. There are several mechanisms responsible for cisplatin resistance and the process of the drug resistance appears to be multifactorial. In this review, we systematically describe and discuss these mechanisms, including the reduced intracellular accumulation of cisplatin, the increased drug detoxification, the alterations in DNA repair and DNA damage response and apoptosis pathways as well as the changes of indirect signal pathways.