Legallicier B, Leclere C, Monteil C, Elkaz V, Morin J P, Fillastre J P
INSERM Unit 295, Faculty of Medicine, University of Rouen, St. Etienne du Rouvray, France.
Drugs Exp Clin Res. 1996;22(2):41-50.
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.
顺铂及其衍生物在人类恶性肿瘤治疗中的应用范围广泛。肾毒性是其最重要的使用限制因素。本研究的目的是比较顺铂（CDDP）和一种新衍生物奥沙利铂（1-OHP）对肾小管近端细胞培养物的影响。使用了三种细胞模型：兔肾原代培养、近端肾小管细胞（RPTC）以及已建立的负鼠肾（OK）和猪肾（LLC-PK1）上皮细胞系。结果表明，在这三种培养系统中，这两种分子的细胞毒性排序与其体内肾毒性一致（CDDP > 1-OHP），但对OK和LLC-PK1细胞的细胞毒性低于对RPTC的细胞毒性。对RPTC的功能和生化评估表明，铂衍生物的毒性作用作用于DNA、蛋白质合成和葡萄糖摄取。1-OHP对DNA合成的作用似乎更有效，但诱导的细胞毒性进展更缓慢。谷胱甘肽依赖性解毒活性的改变可能反映了脂质过氧化过程的发生。本研究表明：1）在研究铂衍生物的肾毒性方面，RPTC比LLC-PK1或OK细胞更合适；2）1-OHP似乎比CDDP具有更强的药理作用。毒性效应比似乎表明1-OHP比CDDP具有更高的安全性。
