Taurolidine: Mode of administration in mouse tumor models

Abstract

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...

Short-term treatment with taurolidine is associated with liver injury

“…However, one recent publication reported that long-term high-dose treatment with taurolidine caused severe hepatic injury in a murine osteosarcoma model [ 30 ]. Therefore, the authors suggested caution before widespread use of taurolidine as an anti-cancer drug in clinical oncology [ 31 ].…”