MECHANISM OF ANTITUMOR DRUG-ACTION - POISONING OF MAMMALIAN DNA TOPOISOMERASE-II ON DNA BY 4'-(9-ACRIDINYLAMINO)-METHANESULFON-META-ANISIDIDE
MECHANISM OF ANTITUMOR DRUG-ACTION - POISONING OF MAMMALIAN DNA TOPOISOMERASE-II ON DNA BY 4'-(9-ACRIDINYLAMINO)-METHANESULFON-META-ANISIDIDE
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DOI：
10.1073/pnas.81.5.1361
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发表时间：
1984-01-01
期刊：
影响因子：
--
通讯作者：
LIU, LF
中科院分区：
文献类型：
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作者：
NELSON, EM;TEWEY, KM;LIU, LF
插入吖啶衍生物 4''-(9-吖啶氨基)甲磺酰苯胺 (m-AMSA)，但不是其异构体 o-AMSA，是一种有效的抗肿瘤药物，在哺乳动物细胞中刺激 DNA 链断裂的形成，其特征是紧密结合的蛋白质。使用纯化的哺乳动物[人宫颈癌HeLa细胞和小牛胸腺]DNA拓扑异构酶，分析了这些抗肿瘤药物对拓扑异构酶-DNA相互作用的影响。抗肿瘤药物 m-AMSA 可显着刺激拓扑异构酶 II-DNA 复合物的形成，该复合物可在蛋白质变性剂治疗中检测到；单链和双链 DNA 断裂都会产生，并且拓扑异构酶 II 亚基共价连接到断裂 DNA 链的每个 5'' 末端。非细胞毒性异构体 o-AMSA 不会在培养细胞中诱导大量 DNA 断裂，在体外刺激复合物形成方面表现出相应较小的效果。体外和体内研究之间的一致性表明，哺乳动物DNA拓扑异构酶II可能是m-AMSA的主要靶标，并且药物诱导的拓扑异构酶II和DNA之间的复合物形成可能是细胞毒性和其他效应（例如DNA序列重排和姐妹染色单体交换）的原因。
The intercalative acridine derivative 4''-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA), but not its isomer o-AMSA, is a potent antitumor drug that in mammalian cells stimulates the formation of DNA strand breaks that are characterized by tightly bound proteins. Using purified mammalian [human cervical carcinoma HeLa cells and calf thymus] DNA topoisomerases, the effects of these antitumor drugs on topoisomerase-DNA interactions were analyzed. The antitumor drug m-AMSA dramatically stimulates the formation of a topoisomerase II-DNA complex that is detected on protein-denaturant treatment; both single- and double-stranded DNA breaks are produced and a topoisomerase II subunit is linked covalently to each 5'' end of the broken DNA strands. The noncytotoxic isomer, o-AMSA, which does not induce significant amounts of DNA breaks in cultured cells, exhibits a correspondingly smaller effect in stimulating formation of the complex in vitro. The agreement between in vitro and in vivo studies suggests that mammalian DNA topoisomerase II may be the primary target of m-AMSA and that the drug-induced complex formation between topoisomerase II and DNA may be the cause of cytotoxicity and other effects such as DNA sequence rearrangements and sister-chromatid exchange.