van der Zee A G, Hollema H H, de Bruijn H W, Willemse P H, Boonstra H, Mulder N H, Aalders J G, de Vries E G
Department of Gynecology, University Hospital, Groningen, The Netherlands.
Gynecol Oncol. 1995 Aug;58(2):165-78. doi: 10.1006/gyno.1995.1205.
The aim of the study is to review the mechanisms of resistance to four classes of drugs that are widely used in ovarian carcinoma: platinum (cisplatin/carboplatin) compounds, classical alkylating agents (cyclophosphamide/melphalan), natural drugs (doxorubicin), and "new drugs" (taxol and taxotere). Both platinum and classical alkylating agents mediate their cytotoxicity by the formation of drug-DNA adducts, resulting in DNA damage. Therefore, drug resistance mechanisms are (in part) comparable. In ovarian carcinoma cell lines increased repair of DNA damage and increased detoxification by binding of drugs to glutathione, possibly catalyzed by glutathione S-transferases, have been identified as the most prominent resistance mechanisms to these drugs. Studies on the role of DNA repair mechanisms and glutathione in human ovarian carcinoma are hampered by the complexity of enzyme systems involved in DNA repair and intratumor heterogeneity for glutathione. Resistance to doxorubicin appears to be mediated by enhanced efflux from the cell by increased expression of membrane glycoproteins acting as a drug efflux pump, such as P-glycoprotein. Resistance to doxorubicin can also be due to quantitative and/or qualitative changes in the nuclear target of doxorubicin, topisomerase (Topo) II. Finally, resistance to taxol may be mediated by enhanced expression of P-glycoprotein, while presumed other mechanisms such as alterations in tubulin structure, the cellular "target" of taxol, and changes in polymerization of tubulin are still largely unresolved. Several ways to modulate the reviewed resistance mechanisms are also described. In conclusion, this review shows that many cell biological factors may be involved in drug resistance. The relevance of the identification of most of these factors in ovarian carcinoma patients however remains to be established.
铂类（顺铂/卡铂）化合物、经典烷化剂（环磷酰胺/美法仑）、天然药物（阿霉素）和“新药”（紫杉醇和多西他赛）。铂类和经典烷化剂均通过形成药物 - DNA加合物介导其细胞毒性，导致DNA损伤。因此，耐药机制（部分）具有可比性。在卵巢癌细胞系中，DNA损伤修复增加以及药物与谷胱甘肽结合导致解毒增加（可能由谷胱甘肽S - 转移酶催化）已被确定为对这些药物最主要的耐药机制。DNA修复机制和谷胱甘肽在人类卵巢癌中的作用研究受到DNA修复相关酶系统的复杂性以及肿瘤内谷胱甘肽异质性的阻碍。对阿霉素的耐药似乎是由作为药物外排泵的膜糖蛋白表达增加导致细胞外排增强介导的，如P - 糖蛋白。对阿霉素的耐药也可能归因于阿霉素的核靶点拓扑异构酶（Topo）II的数量和/或质量变化。最后，对紫杉醇的耐药可能由P - 糖蛋白表达增强介导，而其他推测机制，如微管蛋白结构改变（紫杉醇的细胞“靶点”）以及微管蛋白聚合变化，在很大程度上仍未得到解决。本文还描述了几种调节上述耐药机制的方法。总之，本综述表明许多细胞生物学因素可能参与耐药。然而，在卵巢癌患者中确定这些因素中的大多数的相关性仍有待确定。
