title: The antineoplastic antibiotic taurolidine promotes lung and liver metastasis in two syngeneic osteosarcoma mouse models and exhibits severe liver toxicity.
abstract: Osteosarcoma (OS) is the most frequent primary bone tumor. Despite multiagent neoadjuvant chemotherapy, patients with metastatic disease have a poor prognosis. Moreover, currently used chemotherapeutics have severe toxic side effects. Thus, novel agents with improved antimetastatic activity and reduced toxicity are needed. Taurolidine, a broad-spectrum antimicrobial, has recently been shown to have antineoplastic properties against a variety of tumors and low systemic toxicity. Consequently, we investigated in our study the antineoplastic potential of taurolidine against OS in two different mouse models. Although both OS cell lines, K7M2 and LM8, were sensitive for the compound in vitro, intraperitoneal application of taurolidine failed to inhibit primary tumor growth. Moreover, it enhanced the metastatic load in both models 1.7- to 20-fold and caused severe liver deformations and up to 40% mortality. Thus, systemic toxicity was further investigated in tumor-free mice histologically, by electron microscopy and by measurements of representative liver enzymes. Taurolidine dose-dependent fibrous thickening of the liver capsule and adhesions and atrophies of the liver lobes were comparable in healthy and tumor-bearing mice. Liver toxicity was further indicated by up to eightfold elevated levels of the liver enzymes alanine transaminase, aspartate transaminase and GLDH in the circulation. Ultrastructural analysis of affected liver tissue showed swollen mitochondria with cristolysis and numerous lipid vacuoles in the cytoplasm of hepatocytes. The findings of our study question the applicability of taurolidine for OS treatment and may suggest the need for caution regarding the widespread clinical use of taurolidine as an antineoplastic agent.
authors: Department of Orthopedics, Laboratory for Orthopedic Research, Balgrist University Hospital, and Institute of Veterinary Pathology, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland. research@balgrist.ch
authors: Matthias J E
authors: MJ
authors: Arlt
authors: Denise K
authors: DK
authors: Walters
authors: Ingo J
authors: IJ
authors: Banke
authors: Patrick
authors: P
authors: Steinmann
authors: Gabor J
authors: GJ
authors: Puskas
authors: Josefine
authors: J
authors: Bertz
authors: Katharina M
authors: KM
authors: Rentsch
authors: Felix
authors: F
authors: Ehrensperger
authors: Walter
authors: W
authors: Born
authors: Bruno
authors: B
authors: Fuchs
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects*; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000473:pathology; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology*; D005260:Female; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000556:secondary; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000556:secondary; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D012516:Osteosarcoma / Q000188:drug therapy* / Q000473:pathology; D013654:Taurine / Q000009:adverse effects / Q000031:analogs & derivatives*; D013829:Thiadiazines / Q000009:adverse effects*; D014407:Tumor Cells, Cultured
chemical_list: D000903:Antibiotics, Antineoplastic; D013829:Thiadiazines; D013654:Taurine; C012566:taurolidine