Swenson D H, Li L H, Hurley L H, Rokem J S, Petzold G L, Dayton B D, Wallace T L, Lin A H, Krueger W C
Cancer Res. 1982 Jul;42(7):2821-8.
CC-1065 (NSC 298223), a potent new antitumor antibiotic produced by Streptomyces zelensis, interacts strongly with double-stranded DNA and appears to exert its cytotoxic effects through disruption of DNA synthesis. We undertook this study to elucidate the sites and mechanisms of CC-1065 interaction with DNA. The binding of CC-1065 to synthetic and native DNA was examined by differential circular dichroism or by Sephadex chromatography with photometric detection. The binding of CC-1065 with calf thymus DNA was rapid, being complete within 2 hr, and saturated at 1 drug per 7 to 11 base pairs. The interaction of CC-1065 with synthetic DNA polymers indicated a specificity for adenine- and thymine-rich sites. Agarose gel electrophoresis of CC-1065-treated supercoiled DNA showed that CC-1065 did not intercalate. Site exclusion studies using substitutions in the DNA grooves showed CC-1065 to bind primarily in the minor groove. CC-1065 did not cause DNA breaks; it inhibited susceptibility of DNA to nuclease S1 digestion. It raised the thermal melting temperature of DNA, and it inhibited the ethidium-induced unwinding of DNA. Thus, in contrast to many antitumor agents, CC-1065 stabilized the DNA helix. DNA helix overstabilization may be relevant to the mechanism of action of CC-1065.
CC - 1065（NSC 298223）是由泽链霉菌产生的一种强效新型抗肿瘤抗生素，它与双链DNA强烈相互作用，并且似乎通过干扰DNA合成发挥其细胞毒性作用。我们开展这项研究以阐明CC - 1065与DNA相互作用的位点和机制。通过差示圆二色性或采用光度检测的葡聚糖凝胶色谱法检测CC - 1065与合成DNA和天然DNA的结合。CC - 1065与小牛胸腺DNA的结合迅速，在2小时内完成，并且在每7至11个碱基对有1个药物分子时达到饱和。CC - 1065与合成DNA聚合物的相互作用表明其对富含腺嘌呤和胸腺嘧啶的位点具有特异性。用CC - 1065处理超螺旋DNA后的琼脂糖凝胶电泳表明CC - 1065不发生嵌入。使用DNA沟槽中的取代进行的位点排除研究表明CC - 1065主要结合在小沟中。CC - 1065不会导致DNA断裂；它抑制DNA对核酸酶S1消化的敏感性。它提高了DNA的热解链温度，并且抑制了溴化乙锭诱导的DNA解旋。因此，与许多抗肿瘤药物不同，CC - 1065使DNA螺旋稳定。DNA螺旋过度稳定可能与CC - 1065的作用机制有关。
