The Use of the Epithelial Kidney OK Cell Line for Studying the Nephrotoxicity of Anticancer Platinum Coordination Complexes

Abstract

Nephrotoxicity is one of the most important dose-limiting side-effects of cis-diaminedichloroplatinum (II) (cDDP) in humans. Quiescent OK cells grown in hormonally-defined, serum-free medium in the total absence of antibiotics were used to study the in vitro nephrotoxicity of three platinum complexes which produce different renal toxicity in vivo: cDDP, its stereoisomer trans-diaminedichloroplatinum (II) (tDDP), and cis-diamine-1,1-cyclobutane-dicarboxylateplatinUm (II) (CBDCA). The uptake and cytotoxicity of these compounds at concentrations of 3-l,600μM and their impact on DNA and protein synthesis, glucose uptake, Na+-K+-ATPase and succinate dehydrogenase activities, as well as intracellular total glutathione level, were measured. The results showed that the cytotoxicity ranking of these three compounds, assessed by the LDH release method, was not in agreement with their in vivo nephrotoxic potentials (tDDP > cDDP > CBDCA00 in OK cells versus cDDP > CBDCA > tDDP in vivo). cDDP and tDDP showed similar uptakes at all the concentrations studied, which demonstrated that their cytotoxic potential was not directly related to intracellular levels of platinum. At non-cytotoxic concentrations, both cDDP and CBDCA decreased DNA and protein synthesis and, to a lesser extent, Na+-K+-ATPase activity, whereas no effect on glucose uptake and succinate dehydrogenase activity (a mitochondrial marker enzyme) was observed. Nevertheless, 5–10 times greater concentrations of CBDCA were required to induce effects similar to those induced by cDDP. Our results did not show a rapid and early depletion of intracellular glutathione after exposure to cDDP or CBDCA. tDDP exhibited the characteristics of a non-specific cytotoxic chemical which was unable to markedly inhibit the biochemical and functional parameters studied at non-cytotoxic concentrations. These results underline the key role of the inhibition of synthetic activities in the pathogenesis of cDDP-induced and CBDCA-induced nephrotoxicity in OK cells.