title: Silibinin protects against cisplatin-induced nephrotoxicity without compromising cisplatin or ifosfamide anti-tumour activity.
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.
authors.affiliation: Department of Internal Medicine II, University of Tübingen, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Bokemeyer
authors.forename: L M
authors.initials: LM
authors.lastname: Fels
authors.forename: T
authors.initials: T
authors.lastname: Dunn
authors.forename: W
authors.initials: W
authors.lastname: Voigt
authors.forename: J
authors.initials: J
authors.lastname: Gaedeke
authors.forename: H J
authors.initials: HJ
authors.lastname: Schmoll
authors.forename: H
authors.initials: H
authors.lastname: Stolte
authors.forename: H
authors.initials: H
authors.lastname: Lentzen
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage / Q000633:toxicity*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D018237:Germinoma; D006801:Humans; D007069:Ifosfamide / Q000008:administration & dosage*; D007674:Kidney Diseases / Q000139:chemically induced / Q000517:prevention & control*; D007677:Kidney Function Tests; D007678:Kidney Glomerulus / Q000187:drug effects; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D012838:Silymarin / Q000008:administration & dosage*; D013736:Testicular Neoplasms / Q000188:drug therapy*; D014407:Tumor Cells, Cultured
chemical_list: D012838:Silymarin; D002945:Cisplatin; D007069:Ifosfamide