2001 Volume 47 Issue 4 Pages 378-384
Metallothionein (MT) is known to play an important role in the resistance of tumor cells to cisdiamminedichloroplatinum (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.
