Sinha B K, Politi P M
Cancer Chemother Biol Response Modif. 1990;11:45-57.
After twenty years, understanding the mechanisms of tumor cells kill by anthracyclines still remains an active area of research. Of many mechanisms described for this class of drugs, efforts in the last year have focused on defining the role of free radical formation, topoisomerase II-induced DNA breakage, and P-170-dependent cellular accumulation of anthracyclines in tumor cell kill and resistance. First, in a number of tumor cell lines, the formation of free radical species from anthracyclines has been implicated in the cell killing. Modulation of detoxification pathways in a drug-resistant cell line e.g depletion of GSH, a substrate for peroxidase and transferase, enhanced both the formation of oxy-radicals and adriamycin cytotoxicity. It should be noted, however, that these findings are not true for every cell line examined, and free radical-mediated tumor kill may be cell- or tissue-specific. Second, anthracyclines-mediated topo II-dependent DNA cleavage was observed in most cell lines and reduced breaks were found in resistant cells. The decrease in single-strand breaks, however, neither correlated with the degree of resistance nor with differences in the relative topo II activity, which was in most cases only two-fold less in resistant cells than in sensitive cells. Finally, the reduced accumulation of the drug does not appear to be the only contributing factor in multidrug resistant cells and P-170 is not the only protein overexpressed in certain cells, e.g., an 85,000 Da protein may also be linked to adriamycin resistance. Although GST protein is overexpressed in most adriamycin resistant cells along with mdr1 gene, current evidence suggests that this protein may not be directly involved in adriamycin resistance. Taken together, both the mechanism of action and resistance to this class of drug likely vary among cell lines. Clinical studies in the past year have brought about interesting refinements in anthracycline-containing chemotherapy; ICRF-187 (by itself also cytotoxic) seems to offer protection against cardiac toxicity, while implicating iron in the mediation of cardiac damage. Out of a large number of newer anthracycline derivatives, clinical evidence indicates only a modest increase in therapeutic index with a few analogs, perhaps idarubicin and epirubicin. It is not yet clear that being able to receive more milligrams (or more cycles) of anthracycline eventually translates into a significantly better response rate or in a survival advantage. Much less clear is whether patients refractory to adriamycin may derive any benefit from newer anthracyclines.(ABSTRACT TRUNCATED AT 400 WORDS)
二十年来，了解蒽环类药物杀死肿瘤细胞的机制仍是一个活跃的研究领域。在针对这类药物所描述的众多机制中，去年的研究工作集中在确定自由基形成、拓扑异构酶II诱导的DNA断裂以及蒽环类药物的P - 170依赖性细胞蓄积在肿瘤细胞杀伤和耐药性中的作用。首先，在许多肿瘤细胞系中，蒽环类药物形成自由基与细胞杀伤有关。在耐药细胞系中调节解毒途径，例如耗尽谷胱甘肽（一种过氧化物酶和转移酶的底物），可增强氧自由基的形成和阿霉素的细胞毒性。然而，应该注意的是，这些发现并非对每个检测的细胞系都成立，自由基介导的肿瘤杀伤可能具有细胞或组织特异性。其次，在大多数细胞系中观察到蒽环类药物介导的拓扑异构酶II依赖性DNA切割，而在耐药细胞中切割减少。然而，单链断裂的减少既与耐药程度无关，也与相对拓扑异构酶II活性的差异无关，在大多数情况下，耐药细胞中的拓扑异构酶II活性仅比敏感细胞低两倍。最后，药物蓄积减少似乎不是多药耐药细胞中的唯一影响因素，而且P - 170也不是某些细胞中唯一过度表达的蛋白质，例如一种85,000道尔顿的蛋白质也可能与阿霉素耐药性有关。尽管谷胱甘肽S转移酶蛋白与mdr1基因一起在大多数阿霉素耐药细胞中过度表达，但目前的证据表明该蛋白可能不直接参与阿霉素耐药性。综上所述，这类药物的作用机制和耐药性在不同细胞系中可能有所不同。过去一年的临床研究为含蒽环类药物的化疗带来了有趣的改进；ICRF - 187（其本身也具有细胞毒性）似乎能预防心脏毒性，同时表明铁在心脏损伤的介导中起作用。在大量更新的蒽环类衍生物中，临床证据表明只有少数类似物（可能是伊达比星和表柔比星）的治疗指数略有提高。目前尚不清楚能够接受更多毫克（或更多疗程）的蒽环类药物最终是否会转化为显著更高的缓解率或生存优势。更不清楚的是，对阿霉素耐药的患者是否能从更新的蒽环类药物中获益。（摘要截选至400字）
