An unexpected biotransformation pathway for tetrachloro-(d,l-trans)-1,2-diaminocyclohexaneplatinum(IV) (tetraplatin) in the L1210 cell line.
Tetrachloro(d,l-trans)-1,2-diaminocyclohexaneplatinum(IV) (tetraplatin) has been considered a prodrug which would be converted rapidly to dichloro(d,l-trans)-1,2-diaminocyclohexaneplatinum(II) [PtCl2(dach)] under physiological conditions. However, the biotransformations of tetraplatin have not been studied in detail. We have followed the intracellular biotransformations of tetraplatin and PtCl2(dach) in the L1210 cell line by a two-step high performance liquid chromatography separation procedure described previously (Mauldin et al., Cancer Res., 48: 5136-5144, 1988). At early times the intracellular biotransformation pathways appeared to be very different in tetraplatin- and PtCl2(dach)-treated cells. The tetraplatin present in the medium initially was taken up preferentially by the L1210 cells. However, no intracellular tetraplatin and very little intracellular PtCl2(dach) were found in the tetraplatin-treated cells. Instead, two previously unidentified biotransformation products predominated at early times. The same biotransformation products were present in cells incubated in Hank's balanced salt solution, so they most likely did not arise from extracellular reactions. The unidentified biotransformation products present in tetraplatin-treated cells at early times appeared to be at the platinum(II) level of oxidation. Model reactions suggested that these compounds could have been formed by platinum(II)-assisted platinum(IV) substitution reactions, followed by reduction of the platinum(IV) complex to the platinum(II) level. Thus, there appear to exist unique features of tetraplatin metabolism which are observed only when tetraplatin is taken up directly by the cell without prior reduction. These reaction products did not react with DNA and presumably represent an inactivation pathway.
Chaney
S G
SG
Department of Biochemistry and Biophysics, School of Medicine, University of North Carolina, Chapel Hill 27599.
Gibbons
G R
GR
Wyrick
S D
SD
Podhasky
P
P
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D007939:Leukemia L1210 / Q000378:metabolism*; D009944:Organoplatinum Compounds / Q000378:metabolism* / Q000493:pharmacokinetics*
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; C013933:dichloro-1,2-diaminocyclohexane platinum complex; C049777:ormaplatin