Modification and Uptake of a Cisplatin Carbonato Complex by Jurkat Cells

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area under the curve; article; cell culture; cell surface; concentration response; controlled study; drug binding; drug determination; drug uptake; human; human cell; leukemia cell line; mass spectrometry; molecular weight; priority journal; quantum chemistry; carbon; cisplatin derivative; genomic DNA




The interactions of Jurkat cells with cisplatin, cis-[Pt( 15NH3)2Cl2] (1), are studied using 1H-15N heteronuclear single quantum coherence (HSQC) NMR and inductively coupled plasma mass spectrometry. We show that Jurkat cells in culture rapidly modify the monocarbonato complex cis-[Pt(15NH 3)2(CO3)Cl]- (4), a cisplatin species that forms in culture media and probably also in blood. Analysis of the HSQC NMR peak intensity for 4 in the presence of different numbers of Jurkat cells reveals that each cell is capable of modifying 0.0028 pmol of 4 within ∼0.6 h. The amounts of platinum taken up by the cell, weakly bound to the cell surface, remaining in the culture medium, and bound to genomic DNA were measured as functions of time of exposure to different concentrations of drug. The results show that most of the 4 that has been modified by the cells remains in the culture medium as a substance of molecular mass <3 kDa, which is HSQC NMR silent, and is not taken up by the cell. These results are consistent with a hitherto undocumented extracellular detoxification mechanism in which the cells rapidly modify 4, which is present in the culture medium, so it cannot bind to the cell. Because there is only a slow decrease in the amount of unmodified 4 remaining in the culture medium after 1 h, -1.1 ± 0.4 μM h -1, the cells subsequently lose their ability to modify 4. These observations have important implications for the mechanism of action of cisplatin.

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The article may be found at http://molpharm.aspetjournals.org/content/70/1/348/suppl/DC1


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