PRODUCTION OF PROTEIN-ASSOCIATED DNA BREAKS BY 8-METHOXYCAFFEINE, CAFFEINE AND 8-CHLOROCAFFEINE IN ISOLATED-NUCLEI FROM L1210 CELLS - COMPARISON WITH THOSE PRODUCED BY TOPOISOMERASE-II INHIBITORS
PRODUCTION OF PROTEIN-ASSOCIATED DNA BREAKS BY 8-METHOXYCAFFEINE, CAFFEINE AND 8-CHLOROCAFFEINE IN ISOLATED-NUCLEI FROM L1210 CELLS - COMPARISON WITH THOSE PRODUCED BY TOPOISOMERASE-II INHIBITORS
复制标题
DOI：
10.1093/carcin/12.10.1781
复制
发表时间：
1991-10-01
期刊：
影响因子：
4.7
通讯作者：
POMMIER, Y
中科院分区：
文献类型：
--
作者：
RUSSO, P;POGGI, L;POMMIER, Y
8-甲氧基咖啡因（8-MOC）是一种咖啡因衍生物，比母体化合物更有效，但在诱导DNA单链断裂（SSB），DNA双链断裂（DSB）和DNA-蛋白质交联（DPC）方面与咖啡因非常相似。我们研究了8-MOC、咖啡因和8-氯咖啡因（8-CC）诱导SSBs、DSB和DPC的能力，并与典型的DNA拓扑异构酶Ⅱ抑制剂椭圆藤碱进行了比较。8-MOC的DNA效应与椭圆藤碱相似。在这两种情况下，SSB、DSB和DPC的比例相似，并且在去除药物后迅速可逆。两种化合物的剂量-反应曲线均为钟形。此外，8-MOC、咖啡因和8-CC均能抑制椭圆藤碱诱导的DSB。这些结果是在L1210细胞核水平上获得的。尽管有这些功能上的相似性，8-MOC，咖啡因和8-CC不能刺激形成一个可切割的复合物由纯化的1，1210拓扑异构酶II（p170型）时，SV 40 DNA和人c-myc DNA作为底物。这些甲基化的氧嘌呤可能对不同形式的拓扑异构酶II有活性，或者，它们可能仅在细胞核内的天然染色质“环境”中有活性。
8-Methoxycaffeine (8-MOC) is a caffeine derivative, more potent than the parent compound, but very similar to caffeine in terms of induction of DNA single-strand breaks (SSBs), DNA double-strand breaks (DSBs) and DNA-protein crosslinks (DPCs). We have studied the capability of 8-MOC, caffeine and 8-chlorocaffeine (8-CC) of inducing SSBs, DSBs and DPCs, and we have compared 8-MOC with ellipticine, a typical inhibitor of DNA topoisomerase II. The DNA effects of 8-MOC appeared similar to those of ellipticine. In both cases SSBs, DSBs and DPCs were present in a similar ratio, and they were rapidly reversible after removal of the drug. The dose-response curve was bell-shaped for both compounds. In addition, 8-MOC, caffeine and 8-CC were capable of inhibiting DSBs induced by ellipticine. These results were obtained at the level of L1210 cell nuclei. In spite of these functional similarities, 8-MOC, caffeine and 8-CC were unable to stimulate the formation of a cleavable complex by purified 1,1210 topoisomerase II (p170 form) when SV40 DNA and human c-myc DNA were used as substrate. These methylated oxypurines could be active on a different form of topoisomerase II, or, alternatively, they could be active only in the natural chromatin 'milieu' within the nucleus.