Abstract
Cisplatin is one of the most active cytotoxic agents in the treatment of testicular cancer, but its clinical use is associated with side-effects such as ototoxicity, neurotoxicity and nephrotoxicity. Long-term kidney damage from cisplatin particularly affects the proximal tubular apparatus and can be detected by increased urinary excretion of brush-border enzymes, such as L-alanine-aminopeptidase (AAP), and magnesium. In the current study, the flavonoid silibinin was used as a nephroprotectant for cisplatin-induced nephropathy in a rat animal model. Infusion of silibinin before cisplatin results in a significant decrease in glomerular (indicated by creatinine clearance and serum urea level) and tubular kidney toxicity (excretion of brush-border enzymes and magnesium). Silibinin given alone had no effect on renal function. In order to exclude an inhibition of the anti-tumour activity of cisplatin and 4-hydroperoxy-ifosfamide by co-administration of silibinin, in vitro studies were performed in three established human testicular cancer cell lines. Dose-response curves for cisplatin (3-30 000 nmol) combined with non-toxic silibinin doses (7.25 x 10(-6) or 7.25 x 10(-5) mol l-1) did not deviate significantly from those of cisplatin alone as measured by relative cell survival during a 5 day assay using the sulphorhodamine-B staining technique. Also silibinin did not influence the cytotoxic activity of 4-hydroperoxy-ifosfamide (30-10 000 nmol) in vitro. In summary, these in vitro data rule out a significant inhibition of the anti-tumour activity of the major nephrotoxic components, cisplatin and 4-hydroperoxy-ifosfamide, by co-administration of silibinin in a human germ cell tumour cell line model. Together with these demonstrated cytoprotection effects in the rat animal model, these data form the basis for a randomised clinical trial of silibinin for the protection of cisplatin-associated nephrotoxicity in patients with testicular cancer.
Highlights
Cisplatin led to a decline in kidney function
Silibinin administered alone did not affect any of the investigated parameters of renal function
Animals treated with DDP alone showed a significant reduction in creatinine clearance, which was most pronounced on day 3 following treatment
Summary
In vivo studies on a rat model of DDP nephrotoxicityFemale Wistar rats with an initial body weight between 170 and 230 g were used. The animals only received one injection of the compounds. DDP (Medac, Hamburg, Germany) dissolved in saline was given at a concentration of 5 mg kg-' body weight (b.w.). The compound was dissolved in saline, the animals received about 0.4 mmol silibinin kg-' body weight (=0.2 g silibinin kg-1 b.w). This dose is below the oral maximum tolerated dose (MTD) that was > 1000 mg kg-' body weight (U Mengs, MADAUS AG, Cologne, personal communication). In the group with combined treatment silibinin was given 1 h before the injection of DDP: studies on humans had shown an elimination half-life of 6.3 h (Lorenz et al, 1984). All injections were given i.v. into the tail vein
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