Woynarowski J M, Sigmund R D, Beerman T A
Grace Cancer Drug Center, Roswell Park Memorial Institute, Buffalo, New York 14263.
Biochemistry. 1989 May 2;28(9):3850-5. doi: 10.1021/bi00435a034.
This study demonstrated that agents capable of interacting with the minor groove in nuclear DNA interfere with topoisomerase II mediated effects of antitumor drugs such as VM-26 and m-AMSA. Distamycin, Hoechst 33258, and DAPI were used as agents capable of AT-specific binding in the minor groove of DNA while producing no profound long-range distortion of DNA structure. In intact nuclei from L1210 cells, these minor groove binders inhibited the induction of topoisomerase II mediated DNA damage (DNA-protein cross-links and DNA double-strand breaks) by VM-26 and m-AMSA. The inhibitory effects of distamycin reflected prevention of formation of new lesions but not reversal of preexisting damage. The minor groove binders did not differentiate between lesions induced by an intercalator, m-AMSA, or by a DNA-nonbinding drug, VM-26. All three groove binders inhibited DNA breaks more strongly than DNA-protein cross-links. The inhibitory potency correlated with the size of minor groove binders and the size of their DNA-binding sites: distamycin (5 bp) greater than Hoechst 33258 (4 bp) greater than DAPI (3 bp). The results showed that DNA minor groove binders are a new type of modulators of the action of topoisomerase II targeted drugs.
本研究表明，能够与核DNA小沟相互作用的试剂会干扰拓扑异构酶II介导的抗肿瘤药物（如VM - 26和m - AMSA）的作用。 地霉素、Hoechst 33258和DAPI被用作能够在DNA小沟中特异性结合AT的试剂，同时不会对DNA结构产生严重的长程扭曲。 在L1210细胞的完整细胞核中，这些小沟结合剂抑制了VM - 26和m - AMSA诱导的拓扑异构酶II介导的DNA损伤（DNA - 蛋白质交联和DNA双链断裂）。 地霉素的抑制作用反映了对新损伤形成的预防，而不是对已存在损伤的逆转。 小沟结合剂不能区分由嵌入剂m - AMSA或非DNA结合药物VM - 26诱导的损伤。 所有三种沟结合剂对DNA断裂的抑制作用比对DNA - 蛋白质交联的抑制作用更强。 抑制效力与小沟结合剂的大小及其DNA结合位点的大小相关：地霉素（5 bp）大于Hoechst 33258（4 bp）大于DAPI（3 bp）。 结果表明，DNA小沟结合剂是拓扑异构酶II靶向药物作用的新型调节剂。
