The cellular toxicity of two antitumoural agents derived from platinum, cisplatinum versus oxaliplatinum, on cultures of tubular proximal cells.

There is a large scope for the use for cisplatin and its derivatives in the treatment of human malignancies. Nephrotoxicity is their most important use-limiting factor. The aim of this study has been to compare cisplatin (CDDP) and oxaliplatin (1-OHP), a new derivative, on cultures of tubular proximal cells. Three cells models were used: primary culture of rabbit kidney, proximal tubular cells (RPTC) and established opossum kidney (OK) and pig kidney (LLC-PK1) epithelial cell lines. Results indicate that in these three culture systems, the cytotoxicity-ranking of the two molecules were in agreement with their in vivo nephrotoxicity (CDDP > 1-OHP), but were less cytotoxic for OK and LLC-PK1 cells than for RPTC. Functional and biochemical evaluations in RPTC indicate that toxic effects of platinum derivates are exerted on DNA, protein synthesis and glucose uptake. 1-OHP effect on DNA synthesis seems to be more effective, but induced a more progressive cytotoxicity. Alteration of glutathione-dependent detoxication activities may reflect the occurrence of a lipid peroxidation process. The present study showed that 1) RPTC are more suitable that LLC-PK1 or OK cells for investigating the nephrotoxicity of platinum derivatives; 2) 1-OHP seems to have a more powerful pharmacological effect than CDDP. The toxic effect ratio seems to promise greater safety with 1-OHP than with CDDP.

Modulation of glycolysis induction in primary cultures of rabbit kidney proximal tubule cells: the role of shaking, glucose and insulin.

We have assessed the impact of increasing oxygen availability on cellular phenotype expression of rabbit proximal tubule cells in primary culture developed with variable glucose and/or insulin contents. To mitigate hypoxia at the cell/medium interface, cells were shaken for the whole culture duration and their expressed phenotype was compared with those expressed by static cultures. O2 and CO2 tensions were kept constant in the incubator atmosphere. Glycolysis and gluconeogenesis pathways, detoxication system, and mitochondrial, apical and basolateral membrane marker enzyme activities were assessed. This study showed that the induction of glycolysis which appear in primary cultures of proximal tubule cells may be partially prevented by continuously shaking the cultures. This effect was more marked in the presence of glucose, suggesting better substrate oxidation in shaken cultures.