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J.Health Sci., 47(4), 378-384, 2001
Characterization of cis-Diamminedichloroplatinum (II)-Resistant Murine Cell Lines Derived from Metallothionein Null Cells
Yukako Yamabe,a Yukihiro Kondo,b Wakako Endo,a Kayo Sasaya,a Nobumasa Imura,a Tatsuya Hasegawa,c Yoshiyuki Seko,c and Seiichiro Himeno*, a
aDepartment of Public Health and Molecular Toxicology, School of Pharmaceutical Sciences, Kitasato University, Tokyo 108-8641, Japan, bDepartment of Urology, Nippon Medical School, Tokyo 113-8602, Japan, and cDepartment of Environmental Biochemistry, Yamanashi Institute of Environmental Sciences, Fujiyoshida 403-0005, Japan
Metallothionein (MT) is known to play an important role in the resistance of tumor cells to cis-diamminedichloroplatinum (II) (CDDP, cisplatin). To identify non-MT factors that play important roles in CDDP resistance, we established CDDP-resistant cell lines from simian virus 40-transformed MT null cells. Subclones of CDDP-resistant MT null cells, designated as MKCr-3, -12, and -18, exhibited 24- to 62-fold resistance to CDDP compared with parental cells. The contents of glutathione (GSH) and the activities of GSH-related enzymes and antioxidant enzymes in MKCr-12 and -18 were higher than those in parental cells. However, MKCr-3 cells did not show any significant increase in the levels of GSH nor in enzyme activities except for superoxide dismutase. Accumulation of platinum in CDDP-resistant subclones was 15-26% of that in parental cells 24 h after administration of CDDP. Eleven other subclones of CDDP-resistant MT null cells also exhibited low accumulation of platinum. These results suggest that the decreased accumulation of CDDP may be a predominant factor in the resistance to CDDP in the absence of MT, an intracellular metal- and free radical-scavenger.
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