A
cisplatin-resistant cell line was established by use of KF-1 cells derived from human
serous cystadenocarcinoma of the ovary. This resistant cell line, designated "KFr," was capable of proliferating in the presence of 1.0 micrograms
cisplatin/ml. It had doubling times of 24.8 and 27.2 hours in the presence of 0.5 and 1.0 micrograms
cisplatin/ml, respectively. The KFr cells had
lactate dehydrogenase (LDH) activities about fourfold higher than those of the parent KF-1 cells. Analysis of the
isozymes of the KFr cells revealed that they had a faint
LDH-3 band in addition to
LDH-4, the only stained band in the parent KF-1 cells. The morphologic characteristics of the KFr cells were an enlarged nucleus and prominent nucleoli, unlike the nucleus and nucleoli of the parent KF-1 cells. The degree of resistance to
cisplatin of the KFr cells was about twenty-fold higher than that of the KF-1 cells, with regard to the concentrations of
cisplatin required for 50% inhibition of cell proliferation. However, when 5 microM
calmodulin antagonists [N-(6-aminohexyl)-1-
naphthalenesulfonamide or N-(6-aminohexyl)-5-chloro-1-
naphthalenesulfonamide] were added in the presence of concentrations of
cisplatin that hardly inhibited cell proliferation, the KFr cell proliferation was markedly inhibited. These results suggest that
cisplatin resistance can be overcome by
calmodulin antagonists.