[Mechanisms for resistance and cross-resistance patterns of cisplatin-resistant tumor lines]

Abstract

Mechanisms for cisplatin resistance were studied using mouse leukemias acquired resistance to the drug. Uptakes of cisplatin by L-1210/DDP and P 388/DDP were significantly decreased, compared with the respective sensitive lines. Glutathione contents in both the resistant lines were 1.7 times more than in the respective sensitive ones. While glutathione contents were reduced to about 10% by incubation of cells with D, L-buthionine-S, R-sulfoximine, sensitivity of the resistant cells remained unchanged. Therefore, glutathione might not relate to the mechanism for resistance in these lines. Cross-resistance patterns of L-1210/DDP and P 388/DDP as well as Colon 26/DDP to cisplatin analogs were investigated. Carrier ligands of the analogs, by which antitumor spectra would be controlled, were different from each other and leaving groups were Cl2, as a rule. As a result, L-1210/DDP showed cross-resistance only to two analogs. In contrast, P 388/DDP did so to all complexes tested. The resistance indices to four analogs were more than 50. Colon 26/DDP also showed cross-resistance to all of them, but the degrees of resistance in this line were lower than those in P 388/DDP. These facts revealed that the pattern of cross-resistance was dependent on each cell line and the completely different patterns were shown between the mouse leukemia resistant lines. It was suggested that in developing a new platinum analog, we should select a carrier ligand to which as many resistant lines would show lack of cross-resistance.