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Title of Journal: J Biol Inorg Chem

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Abbravation: JBIC Journal of Biological Inorganic Chemistry

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Springer-Verlag

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10.1016/0026-2714(80)90604-6

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1432-1327

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Impaired hydrolysis of cisplatin derivatives to aquated species prevents energy-dependent uptake in GLC4 cells resistant to cisplatin

Authors: Elene Pereira-Maia, Arlette Garnier-Suillerot,

Publish Date: 2003/05/17
Volume: 8, Issue:6, Pages: 626-634
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Abstract

It has been widely stated that cisplatin enters cells by passive diffusion, despite some reports supporting a carrier-mediated mechanism. We have determined the rate of uptake of carboplatin (CBDCA), of cisplatin (CDDP) and of aquated forms, at different values of the extracellular pH, in the small lung-cancer cells GLC4 and GLC4/CDDP, cells resistant to CDDP. The rate of CDDP uptake is about 2-fold lower in resistant cells than in sensitive ones; in ATP-depleted cells this rate is about the same for both cell lines. The rate of CBDCA uptake is about 10-fold lower than that of CDDP and is the same in both cell lines independently of the ATP status of the cells. On the other hand, the rate of uptake of the aquated form of CDDP is ~40-fold higher than that of CDDP and is the same in both cell lines, but decreases dramatically in ATP-depleted cells. The plot of the initial rate of uptake of the aquated species as a function of its extracellular concentration shows a tendency to be saturable with km=1.9 mM. In conclusion, our data show that, in sensitive GLC4 cells, passive diffusion of CDDP, probably in its neutral dichloro form, and active uptake of the aquated form contribute to the platinum uptake. The active transport of CDDP involves at least two steps: (1) the hydrolysis of the dichloro species in a deficient Cl− space at the level of the plasma membrane, which is the limiting step, and (2) the active transport of the aquated species. In resistant cells, step (1) should be deficient whereas step (2) is the same as in sensitive cells. For CBDCA this mechanism holds; however, step (1) is so low that the active transport does not contribute to the uptake of CBDCA by cells.This work was supported by Université Paris 13 (France), the CNRS (France) and CNPq (Brazil). We thank Prof. E.G.E. de Vries (Department of Internal Medicine, University Hospital, Groningen, The Netherlands) for the generous gift of the two GLC4 cell lines, GLC4/ADR and CLC4/CDDP.


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