Yu L, Goldberg I H, Dedon P C
Division of Toxicology, Massachusetts Institute of Technology, Cambridge 02139.
J Biol Chem. 1994 Feb 11;269(6):4144-51.
DNA damage in HeLa nuclei and isolated nucleosome core particles has been examined for several members of the enediyne family of antitumor antibiotics: calicheamicin gamma 1I (CAL), esperamicin A1 (ESP A1), esperamicin C (ESP C), and neocarzinostatin (NCS). In nuclei, both NCS and ESP A1 produced DNA damage limited to the linker region of the nucleosome, while CAL and ESP C, an analog of ESP A1 missing the deoxyfucose-anthranilate moiety, damaged both the core and linker DNA. DNA fragments produced by CAL and ESP C in the nucleosome core occurred with a 10-11-nucleotide periodicity similar to that produced by DNase I, while damage produced by NCS and ESP A1 appeared to be limited to the terminal portions of the core DNA. The damage in nuclei is shown to be caused directly by the drugs with little contribution from endogenous factors, such as nucleases and topoisomerases. Features of drug structure that may limit damage to the nucleosome core include the presence of substituents on both sides of the CAL/ESP-type core, and the presence of an intercalating moiety, such as the naphthoate of NCS and possibly the anthranilate of ESP A1.
已对抗肿瘤抗生素烯二炔家族的几个成员，即加利车霉素γ1I（CAL）、埃斯帕霉素A1（ESP A1）、埃斯帕霉素C（ESP C）和新制癌菌素（NCS），在HeLa细胞核和分离的核小体核心颗粒中的DNA损伤情况进行了研究。在细胞核中，NCS和ESP A1均导致DNA损伤局限于核小体的连接区，而CAL和ESP C（ESP A1缺失脱氧岩藻糖 - 邻氨基苯甲酸部分的类似物）则损伤核心DNA和连接区DNA。CAL和ESP C在核小体核心中产生的DNA片段具有与DNase I产生的类似的10 - 11个核苷酸的周期性，而NCS和ESP A1产生的损伤似乎局限于核心DNA的末端部分。研究表明，细胞核中的损伤是由药物直接引起的，内源性因素如核酸酶和拓扑异构酶的作用很小。可能限制对核小体核心损伤的药物结构特征包括CAL/ESP型核心两侧存在取代基，以及存在嵌入部分，如NCS的萘甲酸盐以及可能的ESP A1的邻氨基苯甲酸盐。
