Effect of cilastatin on cisplatin-induced nephrotoxicity and on antitumoral activity.

Abstract

e13535 Background: Cisplatin (CDDP) is a very effective and common treatment in solid malignancies used mostly in breast, ovarian, bladder, esophageal, gastric, head and neck cancer and germ cell tumors. One of the most important side effects of CDDP is the nephrotoxicity, a limitating side effect, especially with high CDDP doses, affecting as much as 30% of the patients. Cilastatin (Cls) is a specific inhibitor of renal dedydrodipeptidase I which prevents hydrolysis of imipenem and its accumulation in the proximal tubule. In this work we show that Cls acts as a nephroprotector against CDDP-induced damage without compromising its antitumor activity. Methods: Primary cultures of proximal tubular cells (PTCs) and cell lines of different malignancies (colon, breast, ovarian, bladder) were cultured with CDDP (1, 10 and 30 μM) in the presence or absence of Cls. Cell viability was assessed with MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide) assay. Wistar rats were treated with 5 mg/Kg of CDDP (single dose) and 75 mg/Kg/12 hours of Cls. We measured body weight, serum albumin, ALT, AST, creatinine, BUN, serum iones and GAP anion as well as urinary creatinine, osmolality, potassium, sodium and urea. Results: Concomitant treatment with Cls reduced CDDP-induced changes in PCTs. Several tumoral cell lines were tested with CDDP and Cls together. Cls did not increase or decreased tumor growth alone or in combination with CDDP. CDDP sensitivity was not affected by Cls. Wistar rats treated with CDDP alone showed loss of weight and significant worsening in renal function tests. Wistar rats experienced less loss of weight and a significant reduction in renal function worsening when treated simultaneously with CDDP and Cls. Liver function tests were not altered by the addition of Cls to the treatment. Conclusions: Our findings suggest that Cls administration might represent a novel strategy in the prevention of CDDP-induced acute renal injury without compromising its antitumor activity. Cls treatment could potentially increase the number of patients undergoing CDDP treatment or maintaining treatment. Further clinical trials for renal function preservation in cancer patients are on development.