Jensen P B, Sørensen B S, Sehested M, Demant E J, Kjeldsen E, Friche E, Hansen H H
Department of Oncology, Finsen Institute, Rigshospitalet, Blegdamsvej, Denmark.
Biochem Pharmacol. 1993 May 25;45(10):2025-35. doi: 10.1016/0006-2952(93)90013-m.
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.
与经典蒽环类药物（阿霉素和柔红霉素）不同，阿柔比星（ACLA）不会刺激拓扑异构酶II（topo II）介导的DNA切割。这种差异对于与topo II相关的耐药性可能很重要，本研究的目的是阐明造成这种差异的药物结构。对各种ACLA类似物进行了以下测试：（a）与纯化的topo II的相互作用，（b）细胞中DNA切割的诱导，（c）细胞摄取，以及（d）细胞毒性。在含有发色团阿克拉酮（AKV）（如ACLA）且在C-10位有羧甲基（COOCH3）的类似物与在C-10位和C-11位有羟基的β-玫瑰树碱酮（RMN）发色团的药物之间观察到了显著差异。因此，含RMN的类似物，包括糖苷配基RMN本身，有效地刺激了topo II介导的DNA切割。相反，含AKV的药物抑制DNA切割并拮抗含RMN药物介导的细胞毒性。在因topo II表型改变（at-MDR）而表现出多药耐药性的OC-NYH/VM细胞中，仅对含RMN的药物出现交叉耐药，而对非DNA切割的含AKV化合物未出现交叉耐药。因此，我们的数据表明，蒽环类药物中的一个结构域对于与topo II的相互作用特别重要，即发色团中的C-10和C-11位，并且进一步表明通过在C-10位进行COOCH3取代可规避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。
