Modulation of mitomycin C-induced multidrug resistance in vitro

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-glycoproteinpositive 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>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.