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铂类药物对非小细胞肺癌细胞中ABC转运蛋白功能的抑制作用

[Inhibition of ABC-transporter(s)' function in non-small cell lung cancer cells by platinum drugs].

作者信息

Bogush T A, Konukhova A V, Ravcheeva A B, Zabotina T N, Kadagidze Z G, Bogush E A, Komov D V, Polotskiĭ B E, Laktionov K K, Davydov M I

机构信息

N.N. Blokhin Russian Cancer Research Center, Russian Academy of Medical Sciences, Moscow.

出版信息

Antibiot Khimioter. 2003;48(10):11-5.

Abstract

With an account of the literature data that platinum drugs react with many cellular targets, including ATP and proteins, the authors suggested that disturbance of the function of energy-dependent ABC-transporters (markers of multidrug resistance, MDR) under the effect of platinum drugs could be a cause of increased efficacy of MDR agents (agents, MDR to which is developed by the classical mechanism) when used in combination with platinum drugs even in the treatment of multidrug resistant lung cancer. The cisplatin and carboplatin effect on accumulation of MDR doxorubicin in cells of non-small cell cancer was studied by flow cytometry with the use of biopsy specimens. The MDR phenotype of the tumors was determined by a change in doxorubicin intracellular accumulation under the action of the ABC-transporter(s)' inhibitors: verapamil and genistein (specific inhibitors of Pgp and MRP respectively) and sodium azide (an inhibitor of all energy-dependent ABC-transporters). The MDR phenotypes, i.e. Pgp-MRP+ or Pgp+MRP+, were detected in all the tumors investigated. Two types of changes in doxorubicin intracellular accumulation under the action of the inhibitors and the platinum drugs were shown: (a) an increase in doxorubicin cytoplasmic accumulation and (b) a change in subcellular distribution of the anthracycline (increased accumulation of doxorubicin in the cell nucleus and its higher binding to DNA). Cisplatin and carboplatin had an inhibitory effect on ABC-transporter(s) in all the tumors investigated but the effect of carboplatin was less pronounced. It was concluded that cisplatin and carboplatin stimulation of doxorubicin intracellular accumulation, as well as a change in subcellular distribution of the anthracycline under the action of the platinum drugs (increased doxorubicin accumulation in the cell nucleus) in multidrug resistant lung tumors could be at least partly explained by inhibition of the MDR transporter(s)' function. The results could provide a basis for the use of the sequential combination cisplatin (or carboplatin)-->doxorubicin in the treatment of multidrug resistant lung cancer.

摘要

鉴于文献数据表明铂类药物可与许多细胞靶点发生反应,包括ATP和蛋白质,作者认为在铂类药物作用下,能量依赖性ABC转运蛋白(多药耐药标记物,MDR)功能的紊乱可能是MDR药物(通过经典机制产生MDR的药物)与铂类药物联合使用时疗效增加的原因,甚至在治疗多药耐药肺癌时也是如此。使用活检标本,通过流式细胞术研究了顺铂和卡铂对非小细胞癌细胞中MDR多柔比星蓄积的影响。肿瘤的MDR表型通过ABC转运蛋白抑制剂作用下多柔比星细胞内蓄积的变化来确定:维拉帕米和染料木黄酮(分别为Pgp和MRP的特异性抑制剂)以及叠氮化钠(所有能量依赖性ABC转运蛋白的抑制剂)。在所研究的所有肿瘤中均检测到MDR表型,即Pgp-MRP+或Pgp+MRP+。显示了抑制剂和铂类药物作用下多柔比星细胞内蓄积的两种变化类型:(a)多柔比星胞质蓄积增加,(b)蒽环类药物亚细胞分布改变(多柔比星在细胞核中的蓄积增加及其与DNA的结合增加)。顺铂和卡铂对所有研究肿瘤中的ABC转运蛋白均有抑制作用,但卡铂的作用不太明显。得出的结论是,顺铂和卡铂刺激多柔比星在细胞内蓄积,以及铂类药物作用下蒽环类药物亚细胞分布的改变(多柔比星在多药耐药性肺癌细胞核中的蓄积增加)至少部分可以通过抑制MDR转运蛋白的功能来解释。这些结果可为顺铂(或卡铂)→多柔比星序贯联合用于治疗多药耐药肺癌提供依据。

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