Multidrug resistance (mdr) genes in human cancer.
Multidrug resistance (mdr) genes in human cancer.
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DOI：
10.1038/bjc.1991.152
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发表时间：
1991-05
影响因子：
8.8
通讯作者：
Herweijer H
中科院分区：
文献类型：
--
作者：
Nooter K;Herweijer H
随着更有效的药物的引入和更好的化疗策略的建立，抗癌药物治疗的结果在过去几年中得到了稳步改善。尽管如此，由于细胞耐药性导致的化疗失败仍然是大多数癌症患者的主要问题。使用对抗癌剂具有抗性的细胞系，已经表征了几种类型的药物抗性，其中包括靶蛋白的改变（Cabral等人，1980; Flintoff和Essani，1980）、载体介导的药物摄取（Redwood和Colvin，1980; Sirotnak等人，1981）、细胞药物代谢（Aronow等人，1984）和细胞修复机制（贝德福德和福克斯，1982）。耐药性研究中一个非常有趣的进展是发现了多药耐药性（MDR）现象（布拉德利等人，1988;货车der Bliek & Borst，1989）。在MDR细胞中，对“天然存在的”药物（例如蒽环类、长春花生物碱、鬼臼毒素和秋水仙碱）的抗性的选择导致对MDR药物家族的其他成员的交叉抗性的发展（Bech-Hansen et al.，1976; Dan 0，1972; Inaba &约翰逊，1977; Skovsgaard，1978）。MDR相关药物在结构上不同，具有不同的细胞内靶点。这些药物的共同点是它们都是从各种天然产物中提取的亲脂性化合物。一般来说，MDR细胞对烷化剂（如苯丁酸氮芥和环磷酰胺）、抗代谢药（如阿糖胞苷、甲氨蝶呤和5-氟尿嘧啶）或顺铂无交叉耐药，典型MDR表型的一个显著特征是与亲本细胞系相比，其蓄积药物的能力降低。这种减少的药物积累很可能是多药耐药性的主要原因（Dan 0，1973;凯塞尔& Bosmann，1970; Riehm & Biedler，1972; Sirotnak等人，1986年，在其他参考文献中）。据推测，药物积聚的减少是由于具有广泛基质特异性的能量依赖性单向药物外排泵的活性所致。该药物泵由分子量为170 kD的跨膜糖蛋白（P-糖蛋白）组成（Chen等人，1986;盖拉赫等人，1986; Gros等人，1986年）。它使用ATP形式的能量通过由跨膜片段形成的通道运输药物（Hamada & Tsuruo，1988; Horio等人，1988年）。
Results of treatment with anticancer agents have steadily improved over the years following the introduction of more effective drugs and theestablishment of better designed chemotherapy strategies. Still, chemotherapy failure due to cellular drug resistance remains a major problem in most cancer patients. Using cell lines made resistant to anticancer agents, several types of drug resistance have been character-ised, among which are alterations in target proteins (Cabral et al., 1980; Flintoff & Essani, 1980), carrier mediated drug uptake (Redwood & Colvin, 1980; Sirotnak et al., 1981), cellular drug metabolism (Aronow et al., 1984) and cellular repair mechanisms (Bedford & Fox, 1982). A very intriguing development in drug resistance research is the discovery of the phenomenon of multidrug resistance (MDR)(Bradley et al., 1988; van der Bliek & Borst, 1989). In MDR cells, selection for resistance to'naturally occurring'drugs, eg anthracyclines, vinca alkaloids, podo-phyllotoxins, and colchicine, results in the development of cross-resistance to other members of the MDR drug family (Bech-Hansen et al., 1976; Dan0, 1972; Inaba & Johnson, 1977; Skovsgaard, 1978). The MDR related drugs are struc-turally dissimilar and have different intracellular targets. What these drugs have in common is thatthey are lipophilic compounds derived from various natural products. In gen-eral, MDR cells are not cross-resistant to alkylating agents (eg chlorambucil and cyclophosphamide), antimetabolites (eg cytarabine, methotrexate, and 5-fluorouracil), or cis-platin.A striking feature of the classical MDR phenotype is its reduced ability to accumulate drugs, as compared to the parent cell lines. This reduced drug accumulation is most likely the main cause of multidrug resistance (Dan0, 1973; Kessel & Bosmann, 1970; Riehm & Biedler, 1972; Sirotnak et al., 1986, among other references). It is assumed that the reduced drug accumulation is due to activity of an energy dependent unidirectional drug efflux pump with broad sub-strate specificity. This drug pump is composed of a trans-membrane glycoprotein (P-glycoprotein) with a molecular weight of 170 kD (Chen et al., 1986; Gerlach et al., 1986; Gros et al., 1986). It uses energy in the form of ATP to transport drugs through a channel formed by the transmem-brane segments (Hamada & Tsuruo, 1988; Horio et al., 1988).