Antony Smitha, Agama Keli K, Miao Ze-Hong, Hollingshead Melinda, Holbeck Susan L, Wright Mollie H, Varticovski Lyuba, Nagarajan Muthukaman, Morrell Andrew, Cushman Mark, Pommier Yves
Laboratory of Molecular Pharmacology, National Cancer Institute, 37 Convent Dr., Bldg. 37, Room 5068, National Institutes of Health, Bethesda, MD 20892-4255, USA.
Mol Pharmacol. 2006 Sep;70(3):1109-20. doi: 10.1124/mol.106.024372. Epub 2006 Jun 23.
Indenoisoquinolines are topoisomerase (Top) I inhibitors developed to overcome some of the limitations of camptothecins and expand their anticancer spectrum. Bis-1,3-{(5,6-dihydro-5,11-diketo-11H-indeno[1,2-c]isoquinoline)-6-propylamino}-propane bis(trifluoroacetate) (NSC 727357) is a novel dimeric indenoisoquinoline derivative with potent antiproliferative activity in the NCI-60 cell line panel, promising hollow fiber activity (score of 32) and activity against xenografts. Submicromolar concentrations of the bisindenoisoquinoline NSC 727357 induce Top1 cleavage complexes at specific sites in biochemical assays. At higher concentrations, inhibition of Top1 catalytic activity and DNA intercalation is observed. NSC 727357 also induces a limited number of Top2-DNA cleavage complexes. In contrast to the effect of other Top1 inhibitors, cells treated with the bisindenoisoquinoline NSC 727357 show an arrest of cell cycle progression in G(1) with no significant inhibition of DNA synthesis after a short exposure to the drug. Moreover, unlike camptothecin and the indenoisoquinoline MJ-III-65 (NSC 706744, 6-[3-(2-hydroxyethyl)aminopropyl]-5,6-dihydro-5,11-diketo-2,3-dimethoxy-(methylenedioxy)-11H-indeno[1,2-c]isoquinoline hydrochloride), the cytotoxicity of bisindenoisoquinoline NSC 727357 is only partially dependent on Top1 and p53, indicating that this drug has additional targets besides Top1 and Top2.
茚并异喹啉是为克服喜树碱的一些局限性并扩大其抗癌谱而开发的拓扑异构酶（Top）I抑制剂。双-1,3-{(5,6-二氢-5,11-二酮-11H-茚并[1,2-c]异喹啉)-6-丙基氨基}-丙烷双（三氟乙酸盐）（NSC 727357）是一种新型二聚茚并异喹啉衍生物，在NCI-60细胞系面板中具有强大的抗增殖活性，具有良好的中空纤维活性（评分32）和对异种移植瘤的活性。亚微摩尔浓度的双茚并异喹啉NSC 727357在生化分析中可在特定位点诱导Top1切割复合物。在较高浓度下，可观察到对Top1催化活性和DNA插入的抑制。NSC 727357还可诱导数量有限的Top2-DNA切割复合物。与其他Top1抑制剂的作用不同，用双茚并异喹啉NSC 727357处理的细胞在G(1)期出现细胞周期进程停滞，在短时间接触该药物后DNA合成无明显抑制。此外，与喜树碱和茚并异喹啉MJ-III-65（NSC 706744，6-[3-(2-羟乙基)氨基丙基]-5,6-二氢-5,11-二酮-2,3-二甲氧基-(亚甲二氧基)-11H-茚并[1,2-c]异喹啉盐酸盐）不同，双茚并异喹啉NSC 727357的细胞毒性仅部分依赖于Top1和p53，表明该药物除了Top1和Top2外还有其他靶点。
