Uptake and metabolism of iproplatin in murine L1210 cells

• Published in: Cancer chemotherapy and pharmacology 1989, Vol.25 (1), p.15-18
• Main Authors: PENDYALA, L, WALSH, J. R, HUQ, M. M, ARAKALI, A. V, COWENS, J. W, CREAVEN, P. J
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; Antineoplastic Agents - analysis; Antineoplastic Agents - pharmacokinetics; Biological and medical sciences; Carbon Radioisotopes; Chromatography, High Pressure Liquid - methods; Drug Stability; General aspects; Leukemia L1210 - metabolism; Medical sciences; Mice; Mice, Inbred DBA; Organoplatinum Compounds - analysis; Organoplatinum Compounds - pharmacokinetics; Pharmacology. Drug treatments; Solubility; Time Factors; Tumor Cells, Cultured
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/BF00694332

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.