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To the Editor,

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 mice1 were based on intraperitoneal (i.p.) treatment regimens that were previously reported to be successful in three different mouse tumor models.2–4

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 tumor-free 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 Calabresi, Nici, Darnowski, and coworkers.2–4 Despite this increase in dose, a significant promotion of lung and liver metastasis was still observed and the mortality was comparable to that in the Darnowski study.3 Thus, even this higher dose, despite reaching the toxic range, did not inhibit tumor progression and metastasis. With regard to toxicity of chemotherapeutics, one also needs to keep in mind that well-established chemotherapeutics like cisplatin or doxorubicin are also used in doses that are toxic and cause severe side effects.5 Thus, the comment of Braumann that “…the doses used in the osteosarcoma (animal) model, were in the toxic range and are therefore not relevant as a guide to caution against the clinical(!) use of taurolidine as an antineoplastic agent” is incomprehensible.

The antineoplastic properties of taurolidine have so far been favorably discussed, for example, “The nontoxic nature of taurolidine makes it a favorable option compared with current chemotherapeutic regimens”6 and the toxicity of taurolidine in preclinical models is rarely described. Moreover, in the data sheet of the commonly available Taurolin 2% solution, a median lethal dose (LD50) of >4000 mg/kg taurolidine in mice upon i.v. injection is specified, but no LD50 for the i.p. application is indicated, although i.p. lavage and instillation are two main applications of Taurolin as an antibiotic. In the short toxicology chapter of the book “Taurolin in the tumor therapy,” the i.v. LD50 in mice is indicated with >2,000 mg/kg taurolidine and ∼4,000 mg/kg for i.p. administration.7 Severe taurolidine-related long-term toxicity is not described. Surprisingly, all these reports lack any detailed information on the rational or design of the experiments on which the reported favorable data are based. However, it is described that further detailed toxicity tests including MTD studies were not done because of “ethical reasons”7 and that, based on the assumed low toxicity of taurolidine, studies on the mutagenicity and carcinogenicity of taurolidine were not even initiated (Taurolin data sheet). In this context, the statement “The i.p. administration, …, is prone to an increased risk of side effects and toxicity” in the letter to the editor is surprising, because i.p. administration is the main route of application for taurolidine when used as an antibiotic, and it was so far most frequently used in preclinical studies investigating the antineoplastic effect of taurolidine.6

Pharmacokinetic studies with radiolabeled taurolidine in mice revealed an estimated half-life in the range of hours,7 which is quite long for rodents and might be even comparable to the half-life in humans.8 In addition, the pharmacokinetic data indicate an accumulation of taurolidine and/or its metabolites in the liver (three to four times higher levels than in the blood) independent of the administration route.7 The question whether taurolidine plasma levels comparable to the in vitro IC50 values for OS cell lines9 could be reached by our treatment regimens (or even by lower doses) is in our opinion not justified in view of the significant metastasis promoting activity and the severe life-threatening toxicity observed in our study.1

Importantly, there is accumulating literature reporting failure of taurolidine as an antineoplastic agent. Several preclinical studies that investigated different application routes [i.v., oral (p.o.), intravesical (i.v.)] and lower dosages of taurolidine failed to demonstrate significant antineoplastic effects.10–13 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. therapy studies.7 Very slow i.v. injection of 15 ml/kg (= 300 mg/kg) before orthotopic tumor cell injection and then three times per week revealed no inhibitory effect, but tended to promote the growth of the tumors.10 Moreover, when taurolidine was directly injected into the bladder, primary tumor growth was significantly enhanced.10 Finally, beside first promising results for taurolidine therapy in humans, there are already also clinical studies reported, which showed no benefit for the cancer patients.14, 15

In conclusion, there is accumulating evidence for failure of taurolidine as an antineoplastic agent comparable to the results reported for synthetic matrix-metalloproteinase inhibitors in clinical phases II and III studies in the late 1990 that ignored negative preclinical data. Therefore, the observed severe side effects of taurolidine in preclinical studies and the lack of information on (long-term) toxicity should be taken more seriously and warn investigators who intend to proceed with studies in humans. Animal studies are the only preclinical tool to estimate the effects and side effects of new drugs in the clinic and data questioning a future use in humans should not be neglected.

Yours sincerely,

Matthias J.E. Arlt Walter Born Bruno Fuchs

References

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  • 1
    Arlt MJ, Walters DK, Banke IJ, et al. The antineoplastic antibiotic taurolidine promotes lung and liver metastasis in two syngeneic osteosarcoma mouse models and exhibits severe liver toxicity. Int J Cancer, in press.
  • 2
    Calabresi P, Goulette FA, Darnowski JW. Taurolidine: cytotoxic and mechanistic evaluation of a novel antineoplastic agent. Cancer Res 2001; 61: 681621.
  • 3
    Darnowski JW, Goulette FA, Cousens LP, et al. Mechanistic and antineoplastic evaluation of taurolidine in the DU145 model of human prostate cancer. Cancer Chemother Pharmacol 2004; 54: 24958.
  • 4
    Nici L, Monfils B, Calabresi P. The effects of taurolidine, a novel antineoplastic agent, on human malignant mesothelioma. Clin Cancer Res 2004; 10: 765561.
  • 5
    Longhi A, Errani C, De Paolis M, et al. Primary bone osteosarcoma in the pediatric age: state of the art. Cancer Treat Rev 2006; 32: 42336.
  • 6
    Neary PM, Hallihan P, Wang JH, et al. The evolving role of taurolidine in cancer therapy. Ann Surg Oncol 2010; 17: 113543.
  • 7
    Jacobi CA. Taurolidin in der Tumortherapie. Vorstellung eines neuen Therapiekonzeptes, 1st edn. Bremen: UNI-MED Verlag, 2003.
  • 8
    Stendel R, Scheurer L, Schlatterer K, et al. Pharmacokinetics of taurolidine following repeated intravenous infusions measured by HPLC-ESI-MS/MS of the derivatives taurultame and taurinamide in glioblastoma patients. Clin Pharmacokinet 2007; 46: 51324.
  • 9
    Walters DK, Muff R, Langsam B, et al. Taurolidine: a novel anti-neoplastic agent induces apoptosis of osteosarcoma cell lines. Invest New Drugs 2007; 25: 30512.
  • 10
    Abramjuk C, Bueschges M, Schnorr J, et al. Divergent effects of taurolidine as potential anti-neoplastic agent: inhibition of bladder carcinoma cells in vitro and promotion of bladder tumor in vivo. Oncol Rep 2009; 22: 40914.
  • 11
    Braumann C, Ordemann J, Wildbrett P, et al. Influence of intraperitoneal and systemic application of taurolidine and taurolidine/heparin during laparoscopy on intraperitoneal and subcutaneous tumour growth in rats. Clin Exp Metastasis 2000; 18: 54752.
  • 12
    Braumann C, Schoenbeck M, Menenakos C, et al. Effects of increasing doses of a bolus injection and an intravenous long-term therapy of taurolidine on subcutaneous (metastatic) tumor growth in rats. Clin Exp Metastasis 2005; 22: 7783.
  • 13
    Chromik AM, Huss S, Osseili H, et al. Oral administration of the anti-proliferative substance taurolidine has no impact on dextran sulfate sodium induced colitis-associated carcinogenesis in mice. J Carcinog 2010; 9: 19.
  • 14
    Braumann C, Gutt CN, Scheele J, et al. Taurolidine reduces the tumor stimulating cytokine interleukin-1beta in patients with resectable gastrointestinal cancer: a multicentre prospective randomized trial. World J Surg Oncol 2009; 7: 32.
  • 15
    Imhof L, Goldinger SM, Baumann K, et al. The antibacterial substance, taurolidine in the second/third-line treatment of very advanced stage IV melanoma including brain metastases: results of a phase 2, open-label study. Melanoma Res 2010; 21: 803.

Matthias J.E. Arlt*, Walter Born*, Bruno Fuchs*, * Department of Orthopedics, Laboratory for Orthopedic Research, Balgrist University Hospital, Zurich, Switzerland.