Oral administration of the anti-proliferative substance taurolidine has no impact on dextran sulfate sodium-induced colitis-associated carcinogenesis in mice

Chromik, Ansgar M.; Huss, Sebastian; Osseili, Hayssam; Daigeler, Adrien; Kersting, S.; Sülberg, D.; Mittelkötter, U.; Herdegen, Thomas; Uhl, Waldemar; Müller, Annette

doi:10.4103/1477-3163.62536

Cited by 2 publications

(2 citation statements)

References 87 publications

(84 reference statements)

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“…Interestingly, also a few other studies failed to show a therapeutic effect of taurolidine in vivo although they could demonstrate an antineoplastic effect on the respective tumor cell lines in vitro. 9, 18, 19 In a recently published study, orthotopic bladder tumor growth in rats was even enhanced by instillation of taurolidine 8. In our study, taurolidine treatment promoted significantly experimental and spontaneous metastasis in two different OS mouse models, and this effect increased with the duration of the treatment.…”

Section: Discussionsupporting

confidence: 63%

The antineoplastic antibiotic taurolidine promotes lung and liver metastasis in two syngeneic osteosarcoma mouse models and exhibits severe liver toxicity

Arlt

Walters

Banke

et al. 2012

Intl Journal of Cancer

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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.Osteosarcoma (OS), a highly malignant bone tumor, is the second most frequent cause of cancer-related death in children and young adolescents. Metastasis, predominantly to the lung and bone, is detected in $ 20% of OS patients at diagnosis.1 Up to 50% of patients develop metastases after completion of initial therapy. (Neo)-adjuvant chemotherapy introduced in the late 1970s has improved the survival rate of patients with localized disease by more than 50% compared to surgery alone, but patients with metastatic disease continue to have a 5-year survival rate below 30%. 1,2 Current chemotherapeutics approved for clinical use, for example, methotrexate, doxorubicin, cisplatin, etoposide and ifosfamide, cause serious side effects including neurotoxicity, cardiotoxicity, hepatotoxicity, nephrotoxicity, hearing loss, sterility and induction of secondary malignancies (reviewed in Refs. 1 and 2). Consequently, novel compounds for more effective treatment of OS with minimal systemic toxicity are urgently needed.Taurolidine [bis(1,1-dioxoperhydro-1,2,4-thiadizinyl-4)methane], a derivative of the amino acid taurin and broad-spectrum antibiotic, has originally been used for prophylactic intraoperative wound lavage and the treatment of severe surgical infections like peritonitis (reviewed in Ref...

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Section: Discussionsupporting

confidence: 63%

The antineoplastic antibiotic taurolidine promotes lung and liver metastasis in two syngeneic osteosarcoma mouse models and exhibits severe liver toxicity

Arlt

Walters

Banke

et al. 2012

Intl Journal of Cancer

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“…and lower dosages of taurolidine failed to demonstrate significant antineoplastic effects. [10][11][12][13] Interestingly, in none of these studies, an MTD was determined in pilot experiments. In a recent study in a model of bladder cancer in rats, 10 the treatment regimen was based on taurolidine concentrations published in human i.v.…”

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confidence: 99%

Taurolidine: Mode of administration in mouse tumor models

Arlt¹,

Born²,

Fuchs³

2012

Intl Journal of Cancer

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Our study protocols with taurolidine for the treatment of osteosarcoma (OS) in two syngeneic OS mouse models with K7M2 cells intravenously (i.v.) injected into BALB/c mice and with LM8 cells subcutaneously (s.c.) inoculated in C3H mice 1 were based on intraperitoneal (i.p.) treatment regimens that were previously reported to be successful in three different mouse tumor models. [2][3][4] Braumann in his letter to the editor criticized that we did not determine the maximal tolerated dose (MTD) in our study and that the doses used were in the toxic range and the data therefore were not relevant in the context of a clinical application. However, Calabresi et al. 2 and Darnowski et al. 3 performed MTD-finding experiments in tumorfree nude mice with taurolidine doses ranging from 5 to 30 mg/mouse/injection ( 217-1,300 mg/kg/injection). In the study of Calabresi et al., 2 a dose of 20 mg taurolidine/ mouse/injection (equivalent to 870 mg/kg) resulted in 13% mortality and was chosen as MTD for their subsequent treatment study in an ovarian carcinoma mouse model with i.p. injected SKOV3 cells. The study of Darnowski et al. 3 determined 500 mg/kg taurolidine as the MTD with <8% mortality. This dose was then used in a subsequent treatment study in a mouse model with s.c. injected DU145 human prostate cancer cells. 3 Moreover, the study by Nici et al., 4 investigating the treatment of malignant mesothelioma with taurolidine, used successfully an i.p. dose of 17.5-20 mg/mouse/injection in nude mice with <10% mortality. All these data taken together, and the fact that 2-day treatment intervals in our and the studies by Darnowski and Nici were the same, show that the taurolidine doses used in our experiments were in the range of previously reported MTD. Unfortunately, none of the three previous or any other study reported data of a toxicological analysis of animals that died during the treatment with taurolidine. If one further considers dose-dependent toxicity of taurolidine in mice, one needs to keep in mind that immunocompetent BALB/c and C3H mice used in our study are in general less sensitive to any kind of treatment than immunodeficient mice, which were used in the three previously reported tumor models. This is supported by the observed 0% mortality in our initial experiment with BALB/ c mice that received 10 mg taurolidine/mouse/injection (equivalent to 500 mg/kg/injection), 1 which was within the MTD range determined in the studies in immunodeficient mice. 2,3 Therefore, based on all these observation, there was no rational to perform an MTD study for the same administration rout in wild-type mice also for ethical reasons.However, it is important to note that the low, apparently nontoxic dose of 500 mg taurolidine/kg/injection failed to inhibit tumor progression and significantly promoted lung metastasis. As this taurolidine dosage was obviously too low to affect metastasis, we increased the dose to 750 mg/kg in the s.c. LM8 OS model, 1 which was an intermediate MTD when compared to the doses used in the studies of Ca...

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Oral administration of the anti-proliferative substance taurolidine has no impact on dextran sulfate sodium-induced colitis-associated carcinogenesis in mice

Cited by 2 publications

References 87 publications

The antineoplastic antibiotic taurolidine promotes lung and liver metastasis in two syngeneic osteosarcoma mouse models and exhibits severe liver toxicity

The antineoplastic antibiotic taurolidine promotes lung and liver metastasis in two syngeneic osteosarcoma mouse models and exhibits severe liver toxicity

Taurolidine: Mode of administration in mouse tumor models

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