Differential expression of collateral sensitivity or resistance to cisplatin in human bladder carcinoma cell lines pre-exposed in vitro to either X-irradiation or cisplatin.

Two sublines were derived from a human bladder carcinoma continuous cell line (RT112-P), one by exposure to fractionated X-irradiation (RT112-DXR8) and the other by continuous exposure to cisplatin (RT112-CP). RT112-DXR8 cells were 1.6- to 2-fold more sensitive to cisplatin and 2 analogues, carboplatin and iproplatin, compared with the parental line, whereas RT112-CP cells were 1.6- to 2.8-fold more resistant to these agents. Uptake of 195mcisplatin was elevated 1.4-fold in RT112-DXR8 cells compared with RT112-P cells whereas uptake into RT112-CP cells was similar to that of the parental line. Binding of 195mcisplatin to DNA was similar in all 3 lines. Levels of reduced glutathione were significantly elevated in RT112-CP cells and significantly reduced in RT112-DXR8 cells compared with the parental cells. In addition, activities of glutathione reductase and glutathione peroxidase were higher in RT112-CP cells than in the parental cells whereas the activity of glutathione-S-transferase was similar in all 3 cell lines. A 2.5-fold greater induction of DNA-DNA interstrand crosslinks occurred in RT112-DXR8 cells compared with the parental line, whereas crosslinking in RT112-CP cells, whilst initially similar to that seen in RT112-P cells, was significantly elevated at later times. These findings suggest that mechanisms associated with the expression of resistance and collateral sensitivity to cisplatin may differ.