The activity of verapamil as a resistance modifier in vitro in drug resistant human tumour cell lines is not stereospecific.
The activity of verapamil as a resistance modifier in vitro in drug resistant human tumour cell lines is not stereospecific.
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维拉帕米作为耐药人类肿瘤细胞系体外耐药调节剂的活性不是立体特异性的。
DOI：
10.1016/0006-2952(90)90160-m
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发表时间：
1990
影响因子：
5.8
通讯作者：
S. Kaye
中科院分区：
文献类型：
--
作者：
J. Plumb;Robert Milroyf;S. Kaye
维拉帕米的β-异构体是一种比β-异构体更有效的钙拮抗剂。我们用体外培养的三种耐药细胞系（2780 AD、MCF 7/Adrrrr 1和H6 9 LX 10）检测了维拉帕米的两种立体异构体对化疗药物的增敏作用。外消旋维拉帕米及其单个异构体对亲本细胞系（A2780、MCF 7和NCI-H69）的药物敏感性均无任何影响。维拉帕米（6.6 μM）使所有三种耐药细胞系对阿霉素®的敏感性增加10-12倍。该活性具有浓度依赖性，在6-7 μM时最大。在患者达到的最大血浆浓度2 μM时，灵敏度仅增加2-3倍。6.6 μM维拉帕米单独给药时，左旋和右旋异构体与外消旋维拉帕米同样有效，右旋异构体表现出与外消旋维拉帕米相同的浓度依赖性活性。在维拉帕米（6.6 μM）存在下，2780 AD和MCF 7/Adrr的总细胞Adriamycin®浓度增加两倍。单用左旋和右旋维拉帕米均可使药物蓄积量增加至与外消旋维拉帕米相同的程度。这些结果表明维拉帕米的抗性修饰活性不是立体特异性的。单用右旋维拉帕米可增加维拉帕米的最大耐受血药浓度，因此右旋维拉帕米可能是比外消旋维拉帕米更有效的体内耐药调节剂。
Thel-isomer of verapamil is a more potent calcium antagonist than thed-isomer. We have examined the two stereoisomers of verapamil for their ability to increase the chemosensitivityin vitroof three drug resistant cell lines (2780AD, MCF7/Adrrand H6 9LX10). Neither racemic verapamil nor its individual isomers had any effect on the drug sensitivity of the parent cell lines (A2780, MCF7 and NCI-H69). Verapamil (6.6 μM) increased the sensitivity of all three resistant cell lines to Adriamycin® by 10–12-fold. This activity was concentration dependent and was maximal at 6–7 μM. The increase in sensitivity was only 2–3-fold at 2,μM, the maximum plasma concentration achieved in patients. Both thed- andl-isomers of verapamil alone at 6.6 μM were as effective as racemic verapamil and thed-isomer demonstrated the same concentration dependent activity as racemic verapamil. The total cellular Adriamycin® concentration of both 2780AD and MCF7/Adrrwas increased by two-fold in the presence of verapamil (6.6 μM). Bothd- andl-verapamil alone increased the amount of drug accumulated to the same extent as racemic verapamil. These results indicate that the resistance modification activity of verapamil is not stereospecific. Use ofd-verapamil alone in patients could increase the maximum tolerated plasma concentrations of verapamil and thusd-verapamil may be a more effective resistance modifierin vivothan racemic verapamil.
DOI：
10.1016/s0021-9258(18)61633-3
发表时间：
1987-02
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
M. Cornwell;I. Pastan;M. Gottesman
通讯作者：
M. Cornwell;I. Pastan;M. Gottesman