Role of carrier ligand in platinum resistance in L1210 cells

Abstract

We have examined the effect of carrier ligands on platinum accumulation, incorporation of platinum into DNA, cytotoxicity of Pt-DNA adducts, and repair of Pt-DNA adducts in three L1210 cell lines: L1210/0, which is sensitive to most types of platinum compounds; L1210/DDP, which is resistant to platinum compounds with the ethylenediamine (en) carrier ligand but sensitive to those with the diaminocyclohexane (dach) ligand; and L1210/DACH, which is resistant to dach-Pt compounds but sensitive to en-Pt compounds. There was a selective decrease in accumulation of dach-Pt in the L1210/DACH line and of en-Pt in the L1210/DDP line. Intracellular dach-Pt was incorporated into DNA to a lesser extent than en-Pt in both resistant cell lines. Cytotoxicity of en-Pt adducts was less than that of dach-Pt adducts in the L1210/DDP line, while the reverse was true in the L1210/DACH line. Increased repair was seen in both resistant cell lines; a carrier ligand effect was seen only in the L1210/DDP line, which showed a greater initial rate of repair for en-Pt than dach-Pt adducts. These data suggest that carrier ligand effects seen in resistant cell lines may be due, in part, to differences in accumulation of platinum, repair of Pt-DNA adducts, and tolerance of Pt-DNA adducts.