Taurolidine induces cancer cell death through a variety of mechanisms. Even now, all the antineoplastic pathways it employs are not completely elucidated. It has been shown to enhance apoptosis, inhibit angiogenesis, reduce tumor adherence, downregulate proinflammatory cytokine release, and stimulate anticancer immune regulation following surgical trauma. Apoptosis is activated through both a mitochondrial cytochrome-c-dependent mechanism and an extrinsic direct pathway. A lot of in vitro and animal data support taurolidine's tumoricidal action. Taurolidine has been used as an antimicrobial agent in the clinical setting since the 1970s and thus far appears nontoxic. The nontoxic nature of taurolidine makes it a favorable option compared with current chemotherapeutic regimens. Few published clinical studies exist evaluating the role of taurolidine as a chemotherapeutic agent. The literature lacks a gold-standard level 1 randomized clinical trial to evaluate taurolidine's potential antineoplastic benefits. However, these trials are currently underway. Such randomized control studies are vital to clarify the role of taurolidine in modern cancer treatment.

BackgroundFormer studies already revealed the anti-neoplastic properties of the anti-infective agent Taurolidine (TRD) against many tumor species in vitro and in vivo. Its anti-proliferative and cell death inducing capacity is largely due to its main derivative Taurultam (TRLT). In this study it could be demonstrated, that substance 2250 - a newly defined innovative structural analogue of TRLT - exhibits an anti-neoplastic effect on malignant pancreatic carcinoma in vitro and in vivo.MethodsThe anti-neoplastic potential of substance 2250 as well as its mode of action was demonstrated in extensive in vitro analysis, followed by successful and effective in vivo testings, using xenograft models derived from established pancreatic cancer cell lines as well as patient derived tissue.ResultsOur functional analysis regarding the role of oxidative stress (ROS) and caspase activated apoptosis showed, that ROS driven programmed cell death (PCD) is the major mechanisms induced by substance 2250 in pancreatic carcinoma. What is strongly relevant towards clinical practice is especially the observed inhibition of patient derived pancreatic cancer tumor growth in mice treated with this new substance in combination with its sharply higher metabolic stability.ConclusionThese encouraging results provide new therapeutical opportunities in pancreatic cancer treatment and build the basis for further functional analysis as well as first clinical studies for this promising agent.

Targeting the oxygen stress response pathway is considered a promising strategy to exert antineoplastic activity in a broad spectrum of tumor types. Supporting this view, we summarize the mechanism of action of Taurolidine and Piperlongumine, two antineoplastic agents with strikingly broad tumor selectivity. Taurolidine enhances the oxidative stress (ROS) selectively in tumor cells. Its cytotoxicity for various tumor cells in vitro and in vivo, which includes tumor stem cells, is based on the induction of programmed cell death, largely via apoptosis but also necroptosis and autophagy. The redox-directed mechanism of action of Taurolidine is apparent from the finding that reducing agents e.g., N-acetylcysteine or glutathione impair its cytotoxicity, while its effectiveness is enhanced by agents which inhibit the cellular anti-oxidant capacity. A similar redox-directed antineoplastic action is shown by Piperlongumine, a recently described experimental drug of plant origin. Taurolidine is particularly advantageous in surgical oncology as this taurine-derivative can be applied perioperatively or systemically with good tolerability as shown in initial clinical applications.

a b c d 1 1., E \ t e t ; t3 2 0 5 10 15 0 5 10 15 0 5 0 5 Time (rrin) Figure 2 HPLC chromatograms obtained during the analysis of (a) control plasma and (b) 15 min plasma sample with mobile phase 1 and (c) control plasma and (d) 6 h plasma sample with mobile phase 2. Peak identities: 1. dansylated endogenous material 2. dansyl-DPT 3. dansyl-taurineamide. containing dansyl chloride (1.5 mg) in a tapered centrifuge tube, which was gently shaken for 30 min. Chloroform (4 ml) was added and the procedure for the treatment of plasma samples was followed. Calibration curves were prepared by adding aqueous solutions (100 ul) containing known amounts of taurineamide to distilled water (500 IlI) and control urine (50 ,ul). Because of the difference in polarity between the DPT and taurineamide dansyl derivatives, it was not possible to assay both compounds with a single mobile phase. Examples of chromatograms obtained by this assay for the measurement of DPT and taurineamide concentrations in plasma from a patient who had received 4 g of taurolin by intraperitoneal instillation are shown in Figure 2. The overall derivatisation/extraction yield for taurineamide from plasma was 74% and was independent of the taurineamide concentration up to 100 ,ug ml-'. The overall yield for DPT varied from 19% at 5 ,ug ml-' DPT to 26% at 40 Mg ml-' DPT. Increasing the amount of dansyl chloride, reaction time or the temperature, did not improve the recovery of DPT or taurineamide. The precision (rela-tive standard deviation) of the method estimated from seven replicate analyses was 4.7% for DPT (14.9 ,ug ml-') and 3.7% for tuarineamide (50.6 ug ml-') in blank plasma. Although the overall recovery of DPT is low the precision of the method indicates it is reproducible. Improved sensitivity might result if a fluorescent detector was used in place of a UV detector.

Taurolidine displayed a stable pattern of derivatives in plasma in vitro, whereas in whole blood, a time- and concentration-dependent conversion was apparent. In patients, the calculated average taurolidine plasma concentration, achieved with the repeated infusion regimen, was in the antineoplastic-effective concentration range. The tissue concentrations of taurolidine and taurultame are expected to be higher than the plasma concentrations, taking into account the calculated volumes of distribution. Repeated infusion of taurolidine is the therapeutically adequate mode of administration for the indication of glioblastoma.