INSENSITIVITY OF A MULTIDRUG-RESISTANT CELL-LINE TO CYCLOSPORINE

Background - Multidrug resistance is associated with the over-expression of the P-glycoprotein which may act as an ATP-dependent transporter of many cytotoxic drugs used in cancer chemotherapy. Multidrug resistance can be reversed by a number of agents, including cyclosporin, but the pharmacodynamics and clinical efficacy of reversing agents have not yet been established. Methods - We compared two clonally selected multidrug resistant cell lines, both derived from the same Chinese hamster lung DC-3F cell line. One of these cell lines, DC-3F/VCRd-5L was sensitized to vinblastine by cyclosporin A but the DC-3E/ADX was not. Effects of cyclosporin on the clonal survival, intracellular pH and ATP levels of these two cell lines were compared. Results - Both resistant cell lines had elevated intracellular pH (pH(i)), but only the pH(i) of the DC3F/VCRd-5L cell line was lowered to the level of the sensitive parental line in the presence of cyclosporin A. However, in the presence of a Na+/H-s antiport inhibitor, 5-(N-methyl-N-isobutyl)amiloride (MIBA), cyclosporin A both lowered the pH(i) and sensitized the DC-3F/ADX cell line. Cyclosporin also caused a marked depletion of cellular ATP in conditions of limited ATP synthesis in the DC-3F/VCRd-5L cell line. Under the same conditions, the ATP level of the DC-3F/ADX line was maintained at a level similar to that of the parental line in the absence of drugs.