P-糖蛋白介导多药耐药性的逆转

摘要/Abstract

摘要： 多药耐药 (multidrug resistance, MDR), 即肿瘤细胞在接触一种抗肿瘤药物后产生了耐受其它多种结构全然不同, 作用机理也大相径庭的抗肿瘤药物的抗药性。mdr^-1 基因及由该基因编码的 P-糖蛋白(P-gp, P-Glycoprotein) 是MDR 产生的重要机制之一。P-gp 为能量依赖性药物外排泵, 其功能是使细胞内药物浓度降低, 药物的作用减弱或丧失, 细胞由此获耐药性。因此应用能抑制P-gp 的药物是逆转MDR 的一个重要手段。自1981 年Tsuruo 等报道钙通道阻滞剂维拉帕米能阻断 P-gp 功能逆转小鼠白血病细胞MDR 以来, 寻找和研究抑制P-gp 的药物已成为抗肿瘤药物研究的热点之一。本文就近几年报道的直接与P-gp 相互作用而逆转MDR 的逆转剂作简要介绍, 并讨论逆转 P-gp 介导的MDR 化合物的理化特性及逆转作用的影响因素等诸方面的问题。

关键词: 多药耐药, P-糖蛋白, 逆转剂

Abstract: Multidrug resistance (MDR) is the phe-nomenon observedin tumor cells that describes the simul-taneous emergence of cellular resistance to the cytotoxic attack by structurally and mechanism unrelated chemotherapeutic drugs.The mdr^-1 gene was sufficient to confer the MDR phenotype, including the expression of the P-Glycoprotein (P-Gp).P-Gp appears to play an im-portantrole in tumor cells by acting as an energy-depen-dent efflux pump toremove various drugs from the cell be-fore they have a chance to exert their cytotoxic effects.It is generally accepted that reversal or inhibition of P-Gp function in tumor cells is an important way for modulating MDR.It has been demonstratedin the laboratory that MDR mediated by the P-Gp may be modulated by a wide variety of compounds.These compounds, which include verapamil and cyclosporin, generally have little or no ef-fect by themselves on the tumor cells, but when usedin conjunction with antineoplastic agents, they decrease, andin someinstances eliminate, MDR.This paper will introduce somenew reversal agents and discuss their physical and chemical characteration and others.

Key words: multidrug resistance, P-Glycoprotein, reversal agents

中图分类号:

R979.1

吉兆宁, 刘国卿. P-糖蛋白介导多药耐药性的逆转[J]. 中国临床药理学与治疗学, 2002, 7(3): 269-272.

JI Zhao-Ning, LIU Guo-Qing. Reversal of multidrug resistance mediated by P-Glycoprotein JI Zhao-Ning, LIU Guo-Qing¹[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2002, 7(3): 269-272.

参考文献

1 Bieller HL, Riehm. Cellular esistan to actormycin D in hi-nese hanster cdl in wto; crosresist aoe madioutographic stud-ies, Cancer Res, 1970, 30; 1174-9
2 Ling v, Juliano RL. A suface glyoprotein modulaing drugpermeability in chinese hamster ovary cell mutants. BiochemBiophys Acta, 1978; 455; 1520
3 lhicbaut F, Tsuruo T, Hamada H. Cellular localization d themultidug resistance gene product P-glycopotein in normal hu-man tissue. Proc Natl Acad Sci USA, 1987, 84; 735
4 Tsuno T, Iida H, Tsukagoshis, et al. Overoming of vin-cristine esistance in P388 leukemia in vivo and vitrothroughenhanced cytotoxicity of vincritine and vinblastine by verapamil.Canoer Res, 1981;41: 1967-71
5 Ford JM, Hait W N.Phamacology of dugs that alter multidrugresistance in cancer. Phamacol Rev, 1990, 42, 1551
6 SmithMA, Merry s, Smith JG, et al. Clinically relevant ooncentations of venapamil do not enchance the sensitivity of humanbone marow CFU. GM to adriamycin and VP-16. Br J Cancer,1988; 57; 5762
7 Norimasa S, Tetsuo M, T'atsuto K, et al. 'Two dyridine ana-logues with more effective ability to everse mul tidrug resistanceand with lower calcium channel blocking activity than their dihy-dopyidine countenparts. Cancer Res, 1990; 50; 3055
8 Muller F, Ferandis GE, Comil Scharwtzl, et al.Evidenc fortmanscriptional contol of human mdr I gene expression by verapamil in multidrug esistant leukemia cell. Molecular Phammacol, 1995; 47;51-7
9 Kmnr perumer L, vuban IN, reglion JL, etal. In Vio 1e-versal of mu ltidrug resist nce by twonew dihydopyridine deriva-tives, S16317 and S16324. Aca Oncol, 1994; 3331
10 Yang PM, Li JH, Wang XQ, Resersional effedt of sometradi-tiond medicine on mult idrug resistance in the K562/ADM cellline, Anticancer Drag, 1994,5(suppl l): 350
11 Froidevanx S, Loor F.Myeloidand lymphoid cell alterations innomal mice exposed to chendheraphy with doxorcubicin andor the multidhug resist unce reversing agent SDZPSC833. Int JCancer, 1994; 59; 133-8
12 Kirk J, Syel SK, HarrisAL, et al. Resersa of P-glycopotienmoliated multidrug resistance by pure antioestogens and noveltamoxifen derivatives, Biochem Phamacol, 1994; 48: 27782
13 Gruol Dr, Zee MC, 'TrotterJ, et al. Reversal of multidrug re-sistance by RU486. Cancer Res, 1994; 54; 3088-, 92
14 Galski H, Lazaovici P, Gottesman MM, et al.KT-5720 re-verses mu ltidug esistance in variant S49 mouse lymphoma cellstraunsducod with the human mdr-l cDNA andin human mul-lichitidrug wsistant qaeinoma cells. Eur I Cancer.19951. 380-5
15 MedinJL, Guerci A, MachalS, et al. Comparative evaluartion of S9788, verapamil and cyclosponine A in K562 humanleukemia cell lines in pglywprotei expressing samples fiompatients with hematologic malignancies, Blood, 1994, 84, 262-8
16 Jacques Robert, Multidug resistance reversal. Drug of the Fu-ture, 1997; 22; 149--60
17 Sato W, Fukazawa N, Nakanishi O, et al.Resersal of mul-tidng resistance by a novel qui noline derivative, MS 209. Can-cerChemother Phammacol, 1995; 35; 271-9
18 Catherine M, Barridge G, Higgine CF, et al.The mu ltidrugresist ance agent S R33557 and modulation of vinca alkaloidbi nding to P glyooprotein ly allosteric interaction. Br J Phamna-col, 1997; 122; 7652
19 Klopman G, SrivastavaS, Kolossvany I, et al. Structive activi-ty study and design of mult idrug esistant eversal compounds bya compu ter automated structure evaluation methodology. CancerRes, 1992; 52,4121-5
20 Ramu A, Ramu N.Reversal of mu ltidng esistance by bis(pherylalky 1) amines and stnucturally related compounds.Cancer Chenother Phamaool, 1994; 34: 42330
21 StfaniaS, Akhmed N, Rao US, et al. p glyoprotein sub-strates andantagonists cluster into two distinct groups, Phama-col Exp Ther, 1997;51: 10241
22 Gilles K, Shi LM, Ramu A.Quantitative struct ure activity re-lationship of multidrug esistance revelsal agents. PhamacolExp Ther, 1997; 52; 321
23 Julia AM, Roche H, Berlion M.Multidrug resistance ci cum-vention by a new triazi-noami nopipenidine deivative S9788 in??i tro; definition of the optimal schedule and comparison with ve-rapamil. Br J Cancer, 1994; 69: 868-75
24 Boesch D, Loor F.Extent and persistenccal P glycoprotein in-hi bition in mu ltidrug resistant P388 cells after exposue toresis-tance modifying agents. Anticancer Drug, 1994; 5; 229-35
25 Cardarelli co, Aksentijevich I, Pastan I, et al. Differential ef-fects of P glycopiotein inhibitors on NIH₃T3 cells transfectedwith wild-type (G185) or mutant (V185) mu ltidrug trans-porters. Cancer Res, 1995; 55; 10860
26 Mechetner EB, Roninson IB. Efficient inhibition of P glycopo-tein mediated multidug esistance with a monoclonal antibody.Proc Natl Sci USA, 1992; 89; 5824
27 'lhierny AR, Rahman A, Dritschilo A. Overcoming multidrugresistance in human tumor cell using froe and liposomally eucapsulatedantisense oligodexy nuclootides. Biochem BiophysRes Commun, 1993; 190; 952

[1]	李珊, 柳熠鑫, 任菲菲, 李相晨, 张志清. 天然植物活性成分通过下调 P-糖蛋白逆转肿瘤多药耐药的研究进展[J]. 中国临床药理学与治疗学, 2023, 28(3): 331-340.
[2]	孟强, 刘克辛. 转运体介导药物相互作用的研究现状及展望[J]. 中国临床药理学与治疗学, 2021, 26(8): 876-888.
[3]	李絮，代谊，黄家凤，温纯洁，邹镇，吴兰香，王果，周宏灏. 姜黄素通过调控组蛋白乙酰化修饰上调乳腺癌MCF-7和MCF-7/DOX细胞中MDR1表达[J]. 中国临床药理学与治疗学, 2017, 22(5): 512-517.
[4]	李晖，陈俊，徐彩虹，庞林荣，程晓春. 丹酚酸A抗肿瘤作用及对逆转A549/MTX肿瘤多药耐药的影响[J]. 中国临床药理学与治疗学, 2017, 22(11): 1244-1247.
[5]	朱宏平，靳高凤，陈亚军，李新华，张红，黄世博，夏春华，熊玉卿. 柚皮素对K562/A02细胞MDR1 mRNA/P gp的影响及机制研究[J]. 中国临床药理学与治疗学, 2016, 21(11): 1209-1214.
[6]	王寅声, 李晓智, 沈杰, 李絮, 温纯洁, 吴兰香, 周宏灏. 姜黄素对乳腺癌MCF-7与MCF-7/DOX细胞中P-糖蛋白表达的影响及其机制研究[J]. 中国临床药理学与治疗学, 2015, 20(7): 769-774.
[7]	叶金华，靳高凤，刘名义，朱宏平，陈亚军，冯慧玲，熊玉卿. P-糖蛋白介导阿托伐他汀与阿昔莫司摄取转运的相互作用及其机制研究[J]. 中国临床药理学与治疗学, 2015, 20(12): 1392-1396.
[8]	唐霞, 辛华雯, 李维亮, 欧阳萌. 黄连素对HepG2细胞CYP3A4和P-gp的影响和作用机制研究[J]. 中国临床药理学与治疗学, 2015, 20(1): 7-13.
[9]	戴映, 张晶, 林美钦, 宋洪涛. 环孢素A的药物基因组学与个体化用药的研究现状及进展[J]. 中国临床药理学与治疗学, 2014, 19(8): 931-936.
[10]	王子元, 程卓安, 殷佩浩. 白藜芦醇逆转肿瘤多药耐药的研究进展[J]. 中国临床药理学与治疗学, 2014, 19(6): 717-720.
[11]	王艳, 阳国平, 郭成贤, 裴奇, 章冉冉, 黄路. 口服给药后药-时曲线双峰现象研究进展[J]. 中国临床药理学与治疗学, 2014, 19(3): 341-345.
[12]	李俊, 蒋葵, 张学梅. 多药耐药相关蛋白1及其与肿瘤关系的研究进展[J]. 中国临床药理学与治疗学, 2014, 19(3): 351-355.
[13]	王培培, 许杜娟, 黄灿, 徐文科, 栾家杰. 黄芪皂苷Ⅱ对人肝癌多药耐药细胞BEL-7402/FU的逆转耐药作用[J]. 中国临床药理学与治疗学, 2014, 19(2): 139-144.
[14]	汪辰吟, 陶秀华, 张弦, 汪电雷, 陈金佩, 杨丽丽, 曹银, 汪珊珊. 慢性阻塞性肺疾病进程与肺支气管上皮细胞MRP1功能改变的相关性研究[J]. 中国临床药理学与治疗学, 2014, 19(1): 8-14.
[15]	岑娟, 张峰, 姬汴生. 缺血性中风抗氧化治疗的临床问题及研究进展[J]. 中国临床药理学与治疗学, 2013, 18(4): 448-454.