新型二氢吡啶衍生物替鲁吡啶的R-对映体（GR66234A）和L-对映体（GR66235A）对呈现多药耐药表型的细胞系的作用。

Effects of R-enantiomer (GR66234A) and L-enantiomer (GR66235A) of telupidine, a new dihydropyridine derivative, on cell lines displaying the multidrug resistant phenotype.

作者信息

Tolomeo M, Gancitano R A, Musso M, Porretto F, Perricone R, Abbadessa V, Cajozzo A

机构信息

Interdepartimental Center of Research in Clinical Oncology, University of Palermo, Italy.

出版信息

Haematologica. 1994 Jul-Aug;79(4):328-33.

PMID:7806087

Abstract

BACKGROUND

Many dihydropyridine analogues with calcium channel blocker activity are able to reverse multidrug resistance (MDR). We studied the daunorubicin resistance reversing activity of the R enantiomer (GR66234A) and the L-enantiomer (GR66235 A) of teludipine, a new lipophilic calcium channel blocker synthesized by Glaxo.

METHODS

The daunorubicin resistance reversing activity of the enantiomers of teludipine was evaluated in two MDR cell lines: ARNII, an erythroleukemia cell line which expresses p-glycoprotein, and MCF 7/R, a breast cancer cell line with p-glycoprotein and high levels of glutathione S transferase (GST) and glutathione peroxidase (GSH Px).

RESULTS

GR66234A and GR66235A show the same activity in reversing daunorubicin resistance and are more effective than verapamil. The difference in activity between verapamil and the enantiomers of teludipine is greater in ARNII cells than in MCF 7/R cells. Nevertheless, there are no significative differences in cellular daunorubicin accumulation between ARNII and MCF 7/R following exposure to teludipine, nor are there differences in intracellular daunorubicin distribution in the presence of either MDR reversing agent.

CONCLUSIONS

The low calcium channel antagonistic activity of GR66234A suggests that this compound may be useful in combination with chemotherapy in MDR malignancies.

摘要

背景

许多具有钙通道阻滞剂活性的二氢吡啶类似物能够逆转多药耐药性（MDR）。我们研究了由葛兰素公司合成的新型亲脂性钙通道阻滞剂替地帕明的R对映体（GR66234A）和L对映体（GR66235A）对柔红霉素耐药性的逆转活性。

方法

在两种多药耐药细胞系中评估替地帕明对映体的柔红霉素耐药性逆转活性：ARNII，一种表达P-糖蛋白的红白血病细胞系；以及MCF 7/R，一种具有P-糖蛋白且谷胱甘肽S转移酶（GST）和谷胱甘肽过氧化物酶（GSH Px）水平较高的乳腺癌细胞系。

结果

GR66234A和GR66235A在逆转柔红霉素耐药性方面表现出相同的活性，且比维拉帕米更有效。维拉帕米与替地帕明对映体之间的活性差异在ARNII细胞中比在MCF 7/R细胞中更大。然而，在接触替地帕明后，ARNII和MCF 7/R细胞内柔红霉素的积累没有显著差异，在存在任何一种多药耐药逆转剂的情况下，细胞内柔红霉素的分布也没有差异。