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Role of Carrier Ligand in Platinum Resistance in L1210 Cells¹

Department of Biochemistry and Biophysics, School of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599

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.

¹ This work was supported by Public Health Service Grant CA34082. J. D. P. was supported by a postdoctoral traineeship and S. K. M. by a predoctoral traineeship from NIEHS (Grant 5T32ES07126).

² To whom requests for reprints should be addressed, at Department of Biochemistry and Biophysics, CB 7260, FLOB, University of North Carolina, Chapel Hill, NC 27599-7260.

Received 4/30/90. Accepted 7/16/90.

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