可在酵母中研究靶向DNA拓扑异构酶的抗肿瘤药物。
DNA topoisomerase-targeting antitumor drugs can be studied in yeast.
作者信息
Nitiss J, Wang J C
机构信息
Department of Biochemistry and Molecular Biology, Harvard University, Cambridge, MA 02138.
出版信息
Proc Natl Acad Sci U S A. 1988 Oct;85(20):7501-5. doi: 10.1073/pnas.85.20.7501.
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), 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.
抗肿瘤药物喜树碱和一种苯胺吖啶，即4'-（9-吖啶基氨基）-甲磺酰基间茴香胺（mAMSA），分别作用于DNA拓扑异构酶I和II，已显示出它们能够抑制酿酒酵母突变体的生长，这些突变体是因其对其他抑制剂的通透性而被筛选出来的。除了生长抑制外，这些药物还会诱导高水平的同源重组，并诱导DNA损伤诱导基因DIN3的表达。在同时携带rad52突变的菌株中，这些药物的细胞毒性更为明显。mAMSA的一种类似物，在哺乳动物细胞中作为DNA拓扑异构酶II的抑制剂无效，在这些酵母菌株中引发生理反应时也无效。如果编码DNA拓扑异构酶I的TOP1基因被破坏，喜树碱的生理效应会消失，但mAMSA的不会。这表明DNA拓扑异构酶I是喜树碱细胞毒性的唯一靶点，并说明一种非必需酶仍然可以成为细胞毒性药物的靶点。
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