Dorr R T, Liddil J D
University of Arizona, College of Medicine, Pharmacology Department, Tucson.
Cancer Chemother Pharmacol. 1991;27(4):290-4. doi: 10.1007/BF00685114.
A series of in vitro cytotoxicity studies were performed to achieve pharmacologic reversal of resistance to the alkylating agent mitomycin (MMC) in L-1210 leukemia cells. A multidrug-resistant (MDR), P-glycoprotein-positive cell line, RL-1210/.1 [11], was exposed to potential MDR modulators in the absence or presence of MMC. The following compounds did not reverse MMC-induced MDR: quinine, quinidine, lidocaine, procaine, dimethylsulfoxide (DMSO), dexamethasone, hydrocortisone, prednisolone, estradiol, and testosterone. Three agents were capable of reversing MMC resistance: progesterone, cyclosporin A, and verapamil. The R- and S-isomers of verapamil were equipotent, although they showed a 10-fold difference in cardiovascular potency (S greater than R). Some agents produced cytotoxic effects in MDR cells in the absence of MMC, including progesterone, quinine, and quinidine. The results suggest that R-verapamil and progesterone may have clinical utility in reversing MMC resistance in human tumors. Progesterone may be uniquely efficacious due to (a) its low toxicity in normal cells, (b) its selective cytotoxicity in MDR cells (in the absence of MMC), and (c) its ability to reverse MMC resistance in vitro. The findings also suggest that the P-glycoprotein induced by MMC differs from that induced by doxorubicin, which is highly sensitive to modulation by lysosomotropic amines such as quinine and quinidine.
进行了一系列体外细胞毒性研究，以实现对L-1210白血病细胞中烷化剂丝裂霉素（MMC）耐药性的药理学逆转。一种多药耐药（MDR）、P-糖蛋白阳性细胞系RL-1210/.1 [11]，在不存在或存在MMC的情况下暴露于潜在的MDR调节剂。以下化合物不能逆转MMC诱导的MDR：奎宁、奎尼丁、利多卡因、普鲁卡因、二甲基亚砜（DMSO）、地塞米松、氢化可的松、泼尼松龙、雌二醇和睾酮。三种药物能够逆转MMC耐药性：孕酮、环孢素A和维拉帕米。维拉帕米的R-和S-异构体具有同等效力，尽管它们在心血管效力上显示出10倍的差异（S大于R）。一些药物在不存在MMC的情况下对MDR细胞产生细胞毒性作用，包括孕酮、奎宁和奎尼丁。结果表明，R-维拉帕米和孕酮可能在逆转人类肿瘤中MMC耐药性方面具有临床应用价值。孕酮可能具有独特的疗效，原因如下：（a）其在正常细胞中的低毒性；（b）其在MDR细胞中的选择性细胞毒性（在不存在MMC的情况下）；（c）其在体外逆转MMC耐药性的能力。研究结果还表明，MMC诱导的P-糖蛋白与阿霉素诱导的不同，阿霉素诱导的P-糖蛋白对溶酶体促渗胺如奎宁和奎尼丁的调节高度敏感。
