四价铂前药研究现状与进展

Status and progress of tetravalent platinum prodrugs

以顺铂为代表的二价铂[Pt(Ⅱ)]类药物是现在活跃于一线的抗肿瘤药物,但Pt(Ⅱ)类药物存在不良反应大、生物利用度不佳以及耐药性等问题。四价铂[Pt(Ⅳ)]络合物是Pt(Ⅱ)在轴向位置进行不同取代的衍生物,在肿瘤还原性物质的作用下Pt(Ⅳ)可被还原为Pt(Ⅱ),因此Pt(Ⅳ)可作为Pt(Ⅱ)的前药。Pt(Ⅳ)中轴向取代基的引入可改善Pt(Ⅱ)类药物的药代动力学性质、选择性和生物活性,以及实现除DNA交联之外的附加细胞毒机制,可一定程度上克服Pt(Ⅱ)类药物的耐药性。本文归纳总结了铂类药物的耐药机制,包括铂转运增加、解毒能力增加、自噬增强和DNA修复增强等方面;综述了Pt(Ⅳ)前药的构效关系、主要类型及研究进展,并提出了克服铂类药物耐药性的可能途径。

Bivalent platinum drugs[Pt(Ⅱ)]represented by cisplatin are the first-line drugs in clinical application,but they have defects such as severe side-effects,poor bioavailability and drug resistance.Tetravalent platinum[Pt(Ⅳ)]complexes,derivatives of Pt(Ⅱ)with different substitutions in axial positions,can be reduced to Pt(Ⅱ)under the action of reductants in tumor,and can therefore act as a prodrug of Pt(Ⅱ).Axial substituents can improve platinum drugs’pharmacokinetics,selectivity and bioactivity,as well as achieve anti-tumor effect by additional cytotoxic mechanisms other than DNA damage,which can overcome the drug resistance to Pt(Ⅱ).This review outlines the resistance mechanisms of platinum drugs,including platinum transport,detoxification,autophagy,and DNA repair,etc.It also summarizes the structure-activity relationship,main types and advances of tetravalent platinum prodrugs,as well as possible approach to solve platinum drug resistance.