摘要
喜树碱(CPT)是从植物喜树中分离到的一种生物碱,其化学结构见图1,临床试用发现毒副作用较大,限制了它的应用。近年来由于对其专一作用于拓朴异构酶Ⅰ(Topo-Ⅰ)机制的深入研究,以及合成了一系列具有比喜树碱更强的抗癌活性衍生物和同类物,人们对其进一步发展又引起极大的兴趣。本文就喜树碱及其衍生物研究的最新进展包括作用机制、耐药性和构效关系作扼要介绍。
Earlier studies in cultured mammalian cells have shown that camptothecin (CPT)inhibits both DNA and RNA syntheses and causes reversible fragmentation of DNA. Itwas suggested that the cytotoxicity of the drug is S-phase specific.Recent studiesshowed that in the presence of CPT, putified mammalian DNA topoisomerase I(Topo-I)can induce extensive DNA breaks. It is supposed that CPT can interfere with thebreakage-reunion reaction of Topo--I by the formation of a covalent Tope-I-DNA complex.In the complex Topo-I is linked to the. 3'--phosphoryl end of the broken DNA backbone.Studies of CPT resistant human lymphoblastic leukemia cels and Topo-I delenion,yeaststrains have provided further support that Topo-I is the cytotoxic target of CPT. A cell-free SV40 DNA replication, system was used to study the role of DNA replication indrug action, and:the results suggested that the collision between Topo-I-DNA cleavablecomplexes and moving replication forks results in fork arrest and possibly fork break-age, and such damage is the lethal cause for proliferating cells.Becausa Topo-I is a veryimportant target for the cytotoxic action of the drug,high leveld of the enzyme in severaltypes of human cancer and low levels in correspondihg normal.tissues may provide atherapeutic advantage in cancer treatment with biologically active analogues of CPT.
出处
《肿瘤》
CAS
CSCD
北大核心
1991年第2期74-77,共4页
Tumor
