Rene B, Fosse P, Khelifa T, Jacquemin-Sablon A, Bailly C
Laboratoire de Physicochimie et Pharmacologie des Macromolécules Biologiques, URA 147 CNRS, Institut Gustave Roussy, Villejuif, France.
Mol Pharmacol. 1996 Feb;49(2):343-50.
The mechanism of action of the antitumor drug amsacrine involves intercalation of the acridine chromophore into DNA and inhibition of topoisomerase II. The substituent at position 1' on the aniline is believed to be essential to the formation of the topoisomerase II/DNA cleavable complex and therefore to the cytotoxicity of the drug. To further delineate the role of the 1'-substituent, we investigated the effects on topoisomerase II activities of three anilinoacridine derivatives that differ only by the nature of the substituent at position 1'. The results of the cytotoxicity assays performed with cells sensitive (DC-3F) and resistant [DC-3F/9-hydroxy-ellipticine (9-OH-E)] to topoisomerase inhibitors are correlated with the effects of the drugs on topoisomerase II-mediated DNA cleavage in vitro. The influence of topoisomerase II alpha on the mechanism of action of the drugs was examined using resistant DC-3F/9-OH-E cells transfected with a plasmid carrying a wild-type human topoisomerase II alpha cDNA. Depending on the nature of the 1'-substituent of the drugs, the restoration of normal topoisomerase II alpha catalytic activity in human topoisomerase II alpha cDNA-transfected DC-3F/9-OH-E cells either does not modify the susceptibility of the cells to the drug or partially reverses 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.
抗肿瘤药物安吖啶的作用机制涉及吖啶发色团嵌入DNA以及抑制拓扑异构酶II。苯胺上1'位的取代基被认为对于拓扑异构酶II/DNA可裂解复合物的形成至关重要，因此对于该药物的细胞毒性也至关重要。为了进一步阐明1'位取代基的作用，我们研究了三种仅在1'位取代基性质上有所不同的苯胺吖啶衍生物对拓扑异构酶II活性的影响。用对拓扑异构酶抑制剂敏感（DC - 3F）和耐药[DC - 3F/9 - 羟基玫瑰树碱（9 - OH - E）]的细胞进行细胞毒性试验的结果，与药物在体外对拓扑异构酶II介导的DNA裂解的影响相关。使用携带野生型人拓扑异构酶IIα cDNA的质粒转染的耐药DC - 3F/9 - OH - E细胞，研究了拓扑异构酶IIα对药物作用机制的影响。根据药物1'位取代基的性质，在人拓扑异构酶IIα cDNA转染的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。
