DNA TOPOISOMERASE-TARGETING ANTITUMOR DRUGS CAN BE STUDIED IN YEAST
DNA TOPOISOMERASE-TARGETING ANTITUMOR DRUGS CAN BE STUDIED IN YEAST
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DOI：
10.1073/pnas.85.20.7501
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发表时间：
1988-10-01
影响因子：
11.1
通讯作者：
WANG, JC
中科院分区：
文献类型：
--
作者：
NITISS, J;WANG, JC
抗肿瘤药物喜树碱和一种分别作用于DNA拓扑异构酶I和II的苯胺吖啶，4′-（9-吖啶胺）-甲磺酸-间茴香醚（mAMSA），被证明可以抑制酿酒酵母突变体的生长，因为它们对其他抑制剂具有渗透性。除了抑制生长外，这些药物还诱导高水平的同源重组，并诱导DNA损伤诱导基因DIN3的表达。这些药物的细胞毒性在携带rad52突变的菌株中更为明显。mAMSA的类似物4′-（9-吖啶胺氨基）-甲磺酸-o-茴香醚（oAMSA）在哺乳动物细胞中作为DNA拓扑异构酶II抑制剂无效，在这些酵母菌株中也不能引起生理反应。如果编码DNA拓扑异构酶I的TOP1基因被破坏，喜树碱的生理作用就会消失，而mAMSA则不会。这表明DNA拓扑异构酶I是喜树碱细胞毒性的唯一靶标，并说明非必需酶仍然可以成为细胞毒性药物的靶标。
The antitumor drugs camptothecin and an anilinoacridine, 4''-(9-acridinylamino)-methanesulfon-m-anisidide (mAMSA), which act on DNA topoisomerase I and II, respectively, are shown to inhibit the growth of Saccharomyces cerevisiae mutants selected for their permeability to other inhibitors. In addition to growth inhibition, these drugs induce high levels of homologous recombination and induce the expression of a DNA damage-inducible gene DIN3. Cytotoxicity of the drugs is more pronounced in strains that also carry a rad52 mutation. An analog of mAMSA, 4''-(9-acridinylamino)-methanesulfon-o-anisidide (oAMSA), which is ineffective as an inhibitor of DNA topoisomerase II in mammalian cells, is also ineffective in eliciting physiological responses in these yeast strains. The physiological effects of camptothecin, but not those of mAMSA, disappear if the TOP1 gene encoding DNA topoisomerase I is disrupted. This shows that DNA topoisomerase I is the sole target of camptothecin cytotoxicity and illustrates that a nonessential enzyme can nevertheless be the target for a cytotoxic drug.