Uptake and metabolism of iproplatin in murine L1210 cells.
Iproplatin is structurally unique among the platinum (Pt) agents in the clinic because it is a quadrivalent complex. On the basis of the redox parameters for the Pt(IV) and Pt(II) oxidation states in a chloride system, it has been suggested that Pt(IV) complexes will be reduced to Pt(II) complexes in a biological environment. To test this hypothesis, uptake and metabolism studies of [14C]-iproplatin were carried out in L1210 cells. The L1210 cells raised in DBA2/J mice were incubated in vitro with 50 and 100 microM [14C]-iproplatin at 37 degrees C in Hanks' balanced salt solution, and total uptake and radioactivity associated with acid-insoluble fractions were measured for up to 3 h. Under these conditions, the uptake of iproplatin was linear with time and increased with increasing concentrations of iproplatin in the medium. At all times measured, greater than 35% of radioactivity was associated with the acid-insoluble fraction, suggesting binding to macromolecules. The [14C]-labelled compounds in neutralized acid extracts of cells were separated by reverse-phase high-performance liquid chromatography (HPLC). Three labelled compounds were detected; based on chromatographic elution times, they appeared to be iproplatin, cis-dichloro-bis-isopropylamine platinum(II) (CIP), the reduction product of iproplatin, and a third compound more polar than iproplatin and CIP. The finding of free CIP and the macromolecular binding of radioactivity in the cells suggests that iproplatin is reduced intracellularly.
Pendyala
L
L
Department of Clinical Pharmacology and Therapeutics, Roswell Park Memorial Institute, Buffalo, NY 14263.
Walsh
J R
JR
Huq
M M
MM
Arakali
A V
AV
Cowens
J W
JW
Creaven
P J
PJ
D000818:Animals; D000970:Antineoplastic Agents / Q000032:analysis / Q000493:pharmacokinetics*; D002250:Carbon Radioisotopes; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004355:Drug Stability; D007939:Leukemia L1210 / Q000378:metabolism*; D051379:Mice; D008811:Mice, Inbred DBA; D009944:Organoplatinum Compounds / Q000032:analysis / Q000493:pharmacokinetics*; D012995:Solubility; D013997:Time Factors; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D002250:Carbon Radioisotopes; D009944:Organoplatinum Compounds; C023359:iproplatin