Millard J T, Spencer R J, Hopkins P B
Department of Chemistry, Colby College, Waterville, Maine 04901, USA.
Biochemistry. 1998 Apr 14;37(15):5211-9. doi: 10.1021/bi972862r.
Antitumor agents of the nitrogen mustard family and mitomycin C form interstrand cross-links in duplex DNA. To provide information about the cellular mechanism by which these compounds exert their cytotoxic effects, we examined cross-linking of a nucleosomal core particle formed on a fragment of the 5S RNA gene of Xenopus borealis. For the mustards mechlorethamine, chlorambucil, and melphalan, both sites of monoalkylation and interstrand cross-linking were similar in nucleosomal and free DNA. Some small (two- to three- fold) differences in intensity of cross-linking at some sites were apparent. However, these differences did not appear to correlate with rotational or translational positioning. For mitomycin C, cross-linking was inhibited five- to ten-fold at the nucleosomal dyad and showed attenuation of inhibition toward the ends. Furthermore, rotational positioning also appeared to be a factor, with sites facing inward in the nucleosome less accessible for mitomycin cross-linking. None of these agents demonstrated the 10-base pair periodicity exhibited by hydroxyl radical cleavage of nucleosomal DNA.
氮芥类抗肿瘤药物和丝裂霉素C在双链DNA中形成链间交联。为了提供有关这些化合物发挥细胞毒性作用的细胞机制的信息，我们检测了在北方爪蟾5S RNA基因片段上形成的核小体核心颗粒的交联情况。对于氮芥类药物氮芥、苯丁酸氮芥和美法仑，单烷基化和链间交联的位点在核小体DNA和游离DNA中相似。某些位点的交联强度存在一些小的（两到三倍）差异。然而，这些差异似乎与旋转或平移定位无关。对于丝裂霉素C，在核小体二分体处交联受到五到十倍的抑制，并且在末端抑制作用减弱。此外，旋转定位似乎也是一个因素，核小体中向内的位点对丝裂霉素交联的可及性较低。这些药物均未表现出核小体DNA经羟基自由基切割所呈现的10个碱基对的周期性。
