Nielsen D, Maare C, Skovsgaard T
Department of Oncology R, University of Copenhagen, Denmark.
Gen Pharmacol. 1996 Mar;27(2):251-5. doi: 10.1016/0306-3623(95)02013-6.
The antracyclines induce multiple intracellular effects; however, inhibition of the nuclear enzyme topoisomerase II (TOPO II) is the main mechanism of action. Resistance to anthracyclines in tumor cells is multifactorial. The main mechanisms are: (1) the classic multidrug resistance (MDR) phenotype, which is due to the presence of P-glycoprotein (PGP) in plasma membrane, that is, a "pump" that can extrude a wide range of anticancer drugs. Membrane-active drugs (e.g., verapamil) have been found in vitro to reverse this phenotype. Most clinical studies including chemosensitizers have, however, been disappointing. (2) Non-PGP-mediated MDR: this phenotype is characterized by expression of other proteins in the plasma membrane which are also able to extrude anticancer drugs. (3) Changes in the intracellular distribution of drug: this mechanism has been demonstrated in several cell lines, most often in combination with PGP or non-PGP-mediated resistance. (4) Glutathione transferases (GST) and detoxification mechanisms: these represent a multigene family of enzymes that conjugate glutathione to chemically reactive groups. Direct evidence for a causative role of GST in anthracycline resistance is missing. (5) Alterations in TOPO II (at-MDR): DNA topoisomerases are involved in several aspects of DNA metabolism, in particular genetic recombination, DNA transcription, and chromosome segregation. Low levels of expression or alterations in TOPO II are associated in vitro with resistance. (6) Increased DNA repair: in several cell lines, an increase in the efficacy of DNA repair has been associated with resistance to doxorubicin (DOX). So far, only classic MDR has been shown to contribute to resistance in clinical conditions, whereas evidence for the other mechanisms of resistance is still missing.
蒽环类药物可引发多种细胞内效应；然而，抑制核酶拓扑异构酶II（TOPO II）是其主要作用机制。肿瘤细胞对蒽环类药物的耐药性是多因素的。主要机制如下：（1）经典的多药耐药（MDR）表型，这是由于质膜中存在P-糖蛋白（PGP），即一种能够排出多种抗癌药物的“泵”。体外研究发现膜活性药物（如维拉帕米）可逆转这种表型。然而，包括化学增敏剂在内的大多数临床研究都不尽人意。（2）非PGP介导的MDR：这种表型的特征是质膜中其他蛋白质的表达，这些蛋白质也能够排出抗癌药物。（3）药物细胞内分布的改变：这种机制已在多种细胞系中得到证实，最常见的是与PGP或非PGP介导的耐药性相结合。（4）谷胱甘肽转移酶（GST）与解毒机制：这些代表了一个多基因酶家族，可将谷胱甘肽与化学反应基团结合。目前尚无直接证据表明GST在蒽环类药物耐药中起因果作用。（5）TOPO II的改变（非典型MDR）：DNA拓扑异构酶参与DNA代谢的多个方面，特别是基因重组、DNA转录和染色体分离。TOPO II低水平表达或改变在体外与耐药性相关。（6）DNA修复增加：在多种细胞系中，DNA修复效率的提高与对多柔比星（DOX）的耐药性相关。迄今为止，在临床情况下，只有经典的MDR被证明与耐药性有关，而其他耐药机制的证据仍然缺乏。
