Barancík M, Poleková L, Mrázová T, Breier A, Stankovicová T, Slezák J
Institute for Heart Research, Slovak Academy of Sciences, Bratislava, Slovak Republic.
Drugs Exp Clin Res. 1994;20(1):13-8.
The ability of several Ca(2+)-entry blockers, neuroleptics and local anaesthetics to depress the P-glycoprotein-mediated resistance to vincristine was studied in vitro using the L1210/VCR cell line. This cell line was obtained by long-term adaptation of the L1210 mouse leukaemic cell line on vincristine and showed an overexpression of P-glycoprotein and accompanying multidrug resistance (MDR) which was defined as a cell resistance to several cytostatics such as vincristine, vinblastine and actinomycin D. Efficiency of the drugs applied to reverse this resistance was as follows: for Ca(2+)-entry blockers: verapamil (VER) > or = galopamil (GAL) > flunarizine (FLU) >> diltiazem (DIL) > nimodipine (NIM) > or = nifedipine (NIM); for neuroleptics: trifluoperazine (TFP) > chlorpromazine (CHP) > thioridazine (TRD) > perphenazine (PER); for local anaesthetics: carbanilate-Ca7 > cinchocaine (CIN) >> carbanilate-Ca3 > articaine (ART) > carbanilate CAO > lidocaine (LID). Quaternary cabanilate derivatives (Ca7Q and Ca3Q) with permanent positive charge were found to be unable to reverse the vincristine resistance of L1210/VCR cells. No reasonable correlation between the ability of calcium-entry blockers (DIL, VER, GAL, NIF, NIM and FLU) to reduce the viability of L1210/VCR cells growing in the medium supplemented with vincristine and their reported affinity to the L-type of calcium channel was observed. On the other hand, significant positive correlations were observed between both the inhibitory action of local anaesthetics on propagation of action potential in rat sciatic nerve and the ability of drugs to interact with calmodulin and the ability of the respective drug to reverse the resistance of L1210 cells to vincristine.
使用L1210/VCR细胞系在体外研究了几种钙通道阻滞剂、抗精神病药和局部麻醉药抑制P-糖蛋白介导的对长春新碱耐药性的能力。该细胞系通过将L1210小鼠白血病细胞系长期适应长春新碱而获得，表现出P-糖蛋白的过表达及伴随的多药耐药性（MDR），多药耐药性被定义为细胞对几种细胞抑制剂如长春新碱、长春碱和放线菌素D的耐药性。用于逆转这种耐药性的药物效率如下：对于钙通道阻滞剂：维拉帕米（VER）≥加洛帕米（GAL）＞氟桂利嗪（FLU）＞＞地尔硫䓬（DIL）＞尼莫地平（NIM）≥硝苯地平（NIM）；对于抗精神病药：三氟拉嗪（TFP）＞氯丙嗪（CHP）＞硫利达嗪（TRD）＞奋乃静（PER）；对于局部麻醉药：卡巴尼酯-Ca7＞辛可卡因（CIN）＞＞卡巴尼酯-Ca3＞阿替卡因（ART）＞卡巴尼酯CAO＞利多卡因（LID）。发现带有永久正电荷的季铵卡巴尼酯衍生物（Ca7Q和Ca3Q）无法逆转L1210/VCR细胞对长春新碱的耐药性。在补充了长春新碱的培养基中生长的L1210/VCR细胞，未观察到钙通道阻滞剂（DIL、VER、GAL、NIF、NIM和FLU）降低其活力的能力与其报道的对L型钙通道的亲和力之间存在合理的相关性。另一方面，观察到局部麻醉药对大鼠坐骨神经动作电位传导的抑制作用、药物与钙调蛋白相互作用的能力以及各自药物逆转L1210细胞对长春新碱耐药性的能力之间存在显著的正相关。
