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Rapid Reduction of Tetrachloro(D,L-trans)1,2-diaminocyclohexaneplatinum(IV) (Tetraplatin) in RPMI 1640 Tissue Culture Medium¹

Department of Biochemistry and Nutrition, School of Medicine [G. G., S. G. C.] and Division of Medicinal Chemistry, School of Pharmacy [S. W.], University of North Carolina, Chapel Hill, North Carolina 27599

Tetrachloro(D,L-trans)1,2-diaminocyclohexaneplatinum(IV) (tetraplatin) is a new platinum analogue which is less nephrotoxic than cisplatin and is effective in some cell lines which have become resistant to cisplatin. Since platinum(IV) compounds are thought to require reduction to their platinum(II) analogues for activity, the biotransformations of tetraplatin and its platinum(II) analogue, dichloro(D,L-trans)1,2-diaminocyclohexaneplatinum(II) [PtCl₂(trans-dach)], were studied. For L1210 cells cultured in RPMI 1640 medium, the time course for inhibition of DNA synthesis and cytotoxicity was virtually identical for both drugs. The time course for binding to fetal calf serum in the tissue culture medium was also the same for both drugs. In the complete tissue culture medium, tetraplatin was reduced to PtCl₂(trans-dach) with a half-life of 5 to 15 min, depending on the level of protein sulfhydryl in the medium. The major reducing agent in the medium was the protein sulfhydryl, with glutathione and glucose making minor contributions. No other component of the medium reacted with tetraplatin. The rapid reduction of tetraplatin to PtCl₂(trans-dach) was followed by much slower substitution reactions involving the chloro ligands of PtCl₂(trans-dach). The major transformation products which accumulated in RPMI 1640 medium were identical for both drugs. These data suggest that tetraplatin should be considered a prodrug which is very rapidly converted to PtCl₂(trans-dach) with subsequent biotransformations as expected for the platinum(II) analogue. These data also indicate that in tissue culture most of the tetraplatin is reduced extracellularly.

¹ This research was supported in part by Grant CH-393 from the American Cancer Society.

² To whom requests for reprints should be addressed, at Department of Biochemistry and Nutrition, Campus Box 7260, School of Medicine, University of North Carolina, Chapel Hill, NC 27599.

Received 7/ 7/88. Revised 11/10/88. Accepted 12/13/88.