DIFFERENT MODES OF ANTHRACYCLINE INTERACTION WITH TOPOISOMERASE-II-SEPARATE STRUCTURES CRITICAL FOR DNA-CLEAVAGE, AND FOR OVERCOMING TOPOISOMERASE-II-RELATED DRUG-RESISTANCE
DIFFERENT MODES OF ANTHRACYCLINE INTERACTION WITH TOPOISOMERASE-II-SEPARATE STRUCTURES CRITICAL FOR DNA-CLEAVAGE, AND FOR OVERCOMING TOPOISOMERASE-II-RELATED DRUG-RESISTANCE
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DOI：
10.1016/0006-2952(93)90013-m
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发表时间：
1993-05-25
影响因子：
5.8
通讯作者：
HANSEN, HH
中科院分区：
文献类型：
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作者：
JENSEN, PB;SORENSEN, BS;HANSEN, HH
与经典的蒽环类药物（多柔比星和柔红霉素）相比，阿克拉霉素（ACLA）不刺激拓扑异构酶II（topo II）介导的DNA切割。这种区别可能是重要的拓扑异构酶II相关的耐药性，本研究的目的是澄清负责这种差异的药物结构。测试各种ACLA类似物的：（a）与纯化的拓扑异构酶II的相互作用，（B）细胞中DNA切割的诱导，（c）细胞摄取和（d）细胞毒性。在含有在C-10处具有羧甲基（COOCH 3）的发色团aklavinone（AKV）（例如ACLA）的类似物与具有在C-10和C-11处具有羟基的β-玫瑰霉素酮（RMN）发色团的药物之间观察到显著的区别。因此，含有RMN的类似物，包括糖苷配基RMN本身，有效地刺激拓扑异构酶II介导的DNA切割。相反，含AKV的药物抑制DNA裂解，并拮抗含RMN的药物介导的细胞毒性。在OC-NYH/VM细胞中，由于改变的拓扑异构酶II表型（at-MDR）而表现出多药耐药，仅观察到对含RMN的药物的交叉耐药，而未观察到对含非DNA裂解AKV的化合物的交叉耐药。因此，我们的数据表明，蒽环类药物中的一个结构域对于与拓扑异构体II的相互作用特别重要，即发色团中的C-10和C-11位，并且进一步表明，在C-10位的COOCH 3取代规避了at-MDR。这些发现可能为合成和开发在at-MDR细胞中具有活性的新类似物提供指导。
In contrast to the classic anthracyclines (doxorubicin and daunorubicin), aclarubicin (ACLA) does not stimulate topoisomerase II (topo II) mediated DNA-cleavage. This distinction may be important with respect to topo II-related drug resistance, and the aim of this study was to clarify drug-structures responsible for this difference. Various ACLA analogs were tested for: (a) interaction with purified topo II, (b) induction of DNA cleavage in cells, (c) cellular uptake and (d) cytotoxicity. A remarkable distinction was seen between analogs containing the chromophore aklavinone (AKV) (e.g. ACLA) which have a carboxymethyl group (COOCH3) at C-10 and drugs with a beta-rhodomycinone (RMN) chromophore with hydroxyl groups at C-10 and at C-11. Thus, RMN-containing analogs, including the aglycone RMN itself, effectively stimulated topo II-mediated DNA cleavage. In contrast, AKV-containing drugs inhibited DNA cleavage and antagonized cytotoxicity mediated by RMN-containing drugs. In OC-NYH/VM cells, exhibiting multidrug resistance due to an altered topo II phenotype (at-MDR), cross-resistance was only seen to the RMN-containing drugs whereas no cross-resistance was seen to the non-DNA cleaving AKV-containing compounds. Thus, our data show that one domain in the anthracycline is of particular importance for the interaction with topo II, namely the positions C-10 and C-11 in the chromophore, and further that at-MDR was circumvented by a COOCH3 substitution at position C-10. These findings may provide guidance for the synthesis and development of new analogs with activity in at-MDR cells.