Effects of the enediyne C-1027 on intracellular DNA targets.
Effects of the enediyne C-1027 on intracellular DNA targets.
复制标题
烯二炔 C-1027 对细胞内 DNA 靶标的影响。
DOI：
10.1021/bi00002a025
复制
发表时间：
1995
期刊：
影响因子：
2.9
通讯作者：
Beerman,TA
中科院分区：
文献类型：
--
作者：
CobuzziJr,RJ;Kotsopoulos,SK;Otani,T;Beerman,TA
Revised Manuscript Received October 20, 1994® abstract: We examined DNA damage induced by the enediyne-containingantitumor antibiotic C-1027 in intracellular nuclear and mitochondrial DNA targets using the episome-containing cell line 935.1. Strandscission activity of the C-1027holoantibiotic was measured by the topological forms conversion assay in episomal and mitochondrial DNA, as well as in cell-free plasmid DNA. Genomic DNA damage was quantitated by filter elution analysis. Comparisons were made to the well-characterized enediyne neocarzinostatin. From these studies, mixed single-and double-strand breaks were observed not only in cell-free, plasmid DNA but also in intracellular episomal, mitochondrial, and genomic DNA at low nanomolar concentrations. C-1027 cleaved DNA 285-fold more efficiently incells than in a cell-free environment, and displayed preference for intracellular DNA species in the following rank order: episome> mitochondrial DNA» genomic. NCS also damaged the non-histone-associated mitochondrial DNA, but not the episome. Cleavage of the 935.1 cell episome by C-1027 occurred at specific sites including the BPV origin of replication and E6/E7 open reading frame regions, as well as the MMTV LTR promoter region.Antitumor antibiotics containing bioactive enediyne structures have recently received significant attention due to their remarkable DNA-damaging activities. A potent member of this class of compounds is the microbial derivative C-1027. The biological activities of C-1027 include potent cytotox-icity against cultured human cancer cells (Sugimoto et al., 1990; Zhen et al., 1989) and markedgrowth inhibition of transplantable tumors in mice (Zhen et al., 1989). At the cellular level, C-1027 selectively inhibits nucleic acid synthesis without affecting protein synthesis (Sugimoto et al., 1990; Xu et al., 1990). It also retards cell cycle progression through S-phase and blocks mitosis at the G2+ M boundary (Xu et al., 1990).
