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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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DOI

10.1016/0026-2714(80)90604-6

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1432-1327

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Impaired hydrolysis of cisplatin derivatives to aq

Authors: Elene PereiraMaia Arlette GarnierSuillerot
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 carriermediated 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 lungcancer cells GLC4 and GLC4/CDDP cells resistant to CDDP The rate of CDDP uptake is about 2fold lower in resistant cells than in sensitive ones in ATPdepleted cells this rate is about the same for both cell lines The rate of CBDCA uptake is about 10fold 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 ~40fold higher than that of CDDP and is the same in both cell lines but decreases dramatically in ATPdepleted 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=19 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 cellsThis work was supported by Université Paris 13 France the CNRS France and CNPq Brazil We thank Prof EGE 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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