Choi S U, Lee C O, Kim K H, Choi E J, Park S H, Shin H S, Yoo S E, Jung N P, Lee B H
Screening and Toxicology Research Center, Korea Research Institute of Chemical Technology, Yusong, Korea.
Anticancer Drugs. 1998 Feb;9(2):157-65. doi: 10.1097/00001813-199802000-00007.
The present study was performed to evaluate the ability of KR-30032 and KR-30035 to overcome multidrug resistance (MDR) by measuring the cytotoxicity and the accumulation rate of rhodamine. Additionally, the adverse cardiac toxicity of KR-30032 and KR-30035 was evaluated by measuring the changes of tension in isolated rat aorta and left ventricular pressure (LVP) in guinea pig heart. KR-30035 potentiated the paclitaxel-induced cytotoxicity to HCT15 [P-glycoprotein (P-gp)-expressed cells] to over 15-fold greater than that of verapamil and KR-30032 was equipotent with verapamil (EC50: 0.07, 5.0 and 3.3 nM at 1.0 microg/ml). KR-30032 and KR-30035 were without effect on cytotoxicity to SK-OV-3 cells (P-gp-non-expressing cells), as well as to tamoxifen-induced cytotoxicity in the above cell types. Maximal rhodamine accumulation rates with KR-30032, KR-30035 and verapamil were 290, 291 and 271% in HCT15 cells; and 451, 970 and 440% in HCT15/CL02 cells, respectively. KR-30032 and KR-30035 were 20- to 25-fold less potent than verapamil in relaxing aorta (EC50: 8.13, 6.40 and 0.32 microM, respectively) and were 12- to 35-fold less potent than verapamil in decreasing LVP in isolated hearts (EC50: 41.8, 14.1 and 1.2 microM, respectively). The results of this study suggest that KR-30032 and KR-30035 are active modulators of MDR with potentially minimal cardiovascular toxicity.
本研究旨在通过测量罗丹明的细胞毒性和蓄积率，评估KR - 30032和KR - 30035克服多药耐药性（MDR）的能力。此外，通过测量离体大鼠主动脉张力的变化以及豚鼠心脏左心室压力（LVP），评估KR - 30032和KR - 30035的不良心脏毒性。KR - 30035增强紫杉醇对HCT15细胞（表达P - 糖蛋白（P - gp）的细胞）的细胞毒性，比维拉帕米高15倍以上，而KR - 30032与维拉帕米等效（在1.0微克/毫升时的EC50分别为0.07、5.0和3.3纳摩尔）。KR - 30032和KR - 30035对SK - OV - 3细胞（不表达P - gp的细胞）的细胞毒性以及上述细胞类型中他莫昔芬诱导的细胞毒性均无影响。在HCT15细胞中，KR - 30032、KR - 30035和维拉帕米的最大罗丹明蓄积率分别为290%、291%和271%；在HCT15/CL02细胞中分别为451%、970%和440%。KR - 30032和KR - 30035在舒张主动脉方面的效力比维拉帕米低20至25倍（EC50分别为8.13、6.40和0.32微摩尔），在降低离体心脏LVP方面的效力比维拉帕米低12至35倍（EC50分别为41.8、14.1和1.2微摩尔）。本研究结果表明，KR - 30032和KR - 30035是MDR的活性调节剂，潜在心血管毒性可能最小。
