Taurolidine: Mode of administration in mouse tumor models

To the Editor, The recently published study by Arlt et al. described the effects of the antimicrobial and antiseptic agent taurolidine in a mouse osteosarcoma model. The severe toxicity was observed in tumor-bearing BALB/c mice following intraperitoneal (i.p.) administration of 20 mg/mouse taurolidine on days 1 and 2 (equivalent to 1,000 mg/kg). Similarly, in tumor-bearing and control C3H mice, liver toxicity and mortality were described under i.p. treatment with 750 mg/kg i.p. taurolidine, given in 2-day intervals for up to 25 days. Unfortunately, the authors failed to determine the maximally tolerated dose (MTD) of taurolidine in the respective wildtype mouse strains prior to commencing this experiment on an osteosarcoma model. When the dose dependency of side effects of taurolidine in wild-type mice was analyzed subsequently by subjecting adolescent and adult C3H to a regimen of either a high-dose treatment (750 mg/kg 2-day interval), a medium dose (500 mg/kg 2-day interval), or a low-dose treatment (250 mg/kg daily) for 25 days, the published data point to an MTD of taurolidine in C3H mice to be in the range of 375–400 mg/ kg i.p. The authors’ observations were based on estimated severe liver toxicity and mortality in the high-dose group, milder liver symptoms in the medium dose group and a lack of symptoms in the low-dose group. Clearly, 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. Nevertheless, it is (almost) impossible to suggest data from an animal experiment to human. Evidently, it remains to be seen, whether administration of the MTD i.p. is sufficient to reach the antiproliferative concentration of taurolidine in plasma (IC50 65 lM for osteosarcoma cells in vitro; Ref. 2), to make this model suitable for the determination of the antineoplastic activity of taurolidine. The i.p. administration, as used in the study by Arlt et al. and coworkers, is prone to an increased risk of side effects and toxicity. The short half-life of the drug (1.7–2.2 hr in human blood, Refs. 3,4) requires a continuous administration over a longer period before reaching effective plasma concentrations. The half-life time of pharmaceuticals in mice is significantly shorter than in human (minutes vs. hours). For instance, if taurolidine was administered i.p. to athymic nude mice during 3 weekly cycles (1 weekly cycle comprised three i.p. injections on alternate days) followed by a 2-week drug-free observation period, a dose-dependent mortality was observed in control mice (7.4% mortality at 500 mg/kg per i.p. injection; 37.9% at 600 mg/kg and 50% at 700 mg/kg) (Ref. 5). It is uncommon that MTD was taken as the dose which associates with a 10% mortality rate. An accepted level of toxicity was confirmed in another publication. Alternatively, taurolidine may be administered by the intravenous (i.v.) route to assess its antineoplastic potential in mice tumor models. This mode of administration may also help to determine the extent to which the liver toxicity observed under the high doses taurolidine i.p. used by Arlt et al. may have contributed to the increased metastatic load observed in liver and lung in an osteosarcoma model. The i.v. administration of taurolidine was previously applied in a rodent tumor model. Taurolidine has been used for many years in clinical cases of severe systemic infections in patients such as diffuse peritonitis/sepsis. The recognition of the antineoplastic properties of taurolidine in vitro – at doses below those required for antimicrobial activity – and the confirmation of this activity in several experimental tumor models lead to experimental therapy attempts, first clinical investigations, and a clinical trial. Taurolidine was well-tolerated, and encouraging initial results were reported in patients with pancreatic and stomach cancer, colo-rectal cancer and tumors of the central nervous system.