Involvement of nucleic acid synthesis in cell killing mechanisms of topoisomerase poisons.
Involvement of nucleic acid synthesis in cell killing mechanisms of topoisomerase poisons.
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发表时间：
1990-11
期刊：
影响因子：
11.2
通讯作者：
P. D'Arpa;Chris David Beardmore;Leroy F. Liu
中科院分区：
文献类型：
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作者：
P. D'Arpa;Chris David Beardmore;Leroy F. Liu
喜树碱的主要细胞毒性机制被认为涉及复制机制与喜树碱介导的拓扑异构酶I-DNA可裂解复合体之间的相互作用(Y.H.Hsiang，M.G.Lihou，and L.F.Liu，癌症研究，49：5077-5082,1989)。在目前的研究中，我们证明了拓扑异构酶II毒物4‘-(9-acridinylamino)methanesulfon-m-anisidide(m-AMSA)和依托泊苷对V79细胞的杀伤作用可能不仅涉及正在进行的DNA合成，还涉及正在进行的RNA合成。在核酸合成抑制剂存在的情况下，用拓扑异构酶毒药处理有丝分裂分裂同步的V79细胞。S期V79细胞对拓扑异构酶I和拓扑异构酶II对m-AMSA的敏感性高于G1期细胞。S期细胞对m-AMSA和喜树碱的杀伤敏感性在与APHICOLIN共处理过程中被消除，但在处理后不被消除，这表明正在进行的DNA合成参与了拓扑异构酶I和II毒物对细胞的杀伤。与转录抑制剂5，6-二氯-1-β-D-呋喃核糖基苯并咪唑或虫草素共处理可部分保护m-AMSA的细胞毒作用，但对喜树碱的细胞毒作用无影响。这些结果表明，正在进行的RNA转录可能参与了拓扑异构酶II毒物对细胞的杀伤，而不是拓扑异构酶I毒物。与喜树碱联合处理可降低间-AMSA对G1期V79细胞的细胞毒作用，提示拓扑异构酶I和II之间可能存在拮抗作用。这种拓扑异构酶I和II毒物之间的拮抗作用可以通过喜树碱对RNA转录的强烈抑制来解释。
The primary cytotoxic mechanism of camptothecin has been proposed to involve an interaction between the replication machinery and the camptothecin-mediated topoisomerase I-DNA cleavable complex (Y. H. Hsiang, M.G. Lihou, and L.F. Liu, Cancer Res., 49:5077-5082, 1989). In the present study, we show that killing of V79 cells by the topoisomerase II poisons 4'-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA) and etoposide may involve ongoing RNA synthesis in addition to ongoing DNA synthesis. V79 cells synchronized by mitotic shake-off were treated with topoisomerase poisons in the presence of inhibitors of nucleic acid synthesis. S-Phase V79 cells were more sensitive to the topoisomerase I poison camptothecin and the topoisomerase II poison m-AMSA than G1-phase cells. The greater sensitivity of S-phase cells to killing by m-AMSA and camptothecin was abolished during cotreatment, but not posttreatment, with aphidicolin, suggesting that ongoing DNA synthesis in involved in cell killing by both topoisomerase I and II poisons. Cotreatment with transcription inhibitors, such as 5,6-dichloro-1-beta-D-ribofuranosyl benzimidazole or cordycepin, partially protected cells from the cytotoxic effects of m-AMSA but had no effect on camptothecin-mediated cytotoxicity. These results suggest that ongoing RNA transcription may be involved in cell killing by topoisomerase II poisons but not topoisomerase I poisons. Cotreatment with camptothecin reduced m-AMSA-mediated cytotoxicity in G1-phase V79 cells, suggesting a possible antagonism between topoisomerase I and II poisons. This antagonistic effect between topoisomerase I and II poisons could be explained by the strong inhibitory effect of camptothecin on RNA transcription.