René B, Fossé P, Khélifa T, Jacquemin-Sablon A, Bailly C
Laboratoire de physicochimie et pharmacologie des macromolécules biologiques, URA 147 CNRS, Institut Gustave-Roussy, Villejuif, France.
Bull Cancer. 1997 Oct;84(10):941-8.
Amsacrine is an intercalating planar polycyclic aromatic molecule that displays antitumor activity. The cytotoxicity of this compound is related to its interaction with topoisomerase II. The substituent at position 1' on the aniline is thought to be essential to the formation of the topoisomerase II-DNA cleavable complex and hence the cytotoxicity of the drug. The influence of three substituents at position 1' on the modulation of the activity of topoisomerase II was investigated. The following observations emerge from our structure-activity relationship study: i) the effects of the drugs on topoisomerase II-mediated DNA cleavage in vitro are correlated with the results of the cytotoxicity assays performed with cells sensitive (DC-3F) and resistant to topoisomerase II inhibitors (DC-3F/9-OH-E); ii) depending on the nature of the 1' substituent of the drugs, the restoration of a normal topoisomerase II alpha catalytic activity in resistant DC-3F/9-OH-E cells transfected with a plasmid carrying a wild type topoisomerase II alpha cDNA (hTOP2) either does not modify the susceptibility of the cells to the drug or partially reverse the resistance phenotype. The molecular and cellular studies reveal that topoisomerase II alpha is implicated in the cytotoxicity of amsacrine and confirm that the substituent at position 1' on the anilino ring of amsacrine governs the interaction with topoisomerase II.
安吖啶是一种具有抗肿瘤活性的嵌入型平面多环芳烃分子。该化合物的细胞毒性与其与拓扑异构酶II的相互作用有关。苯胺上1'位的取代基被认为对拓扑异构酶II-DNA可裂解复合物的形成以及药物的细胞毒性至关重要。研究了1'位的三个取代基对拓扑异构酶II活性调节的影响。我们的构效关系研究得出以下观察结果：i）药物对体外拓扑异构酶II介导的DNA裂解的影响与用对拓扑异构酶II抑制剂敏感（DC-3F）和耐药（DC-3F/9-OH-E）的细胞进行的细胞毒性试验结果相关；ii）根据药物1'位取代基的性质，用携带野生型拓扑异构酶IIα cDNA（hTOP2）的质粒转染的耐药DC-3F/9-OH-E细胞中正常拓扑异构酶IIα催化活性的恢复，要么不改变细胞对药物的敏感性，要么部分逆转耐药表型。分子和细胞研究表明，拓扑异构酶IIα与安吖啶的细胞毒性有关，并证实安吖啶苯胺环上1'位的取代基决定了与拓扑异构酶II的相互作用。
