Pharmacokinetics of Taurolidine following Repeated Intravenous Infusions Measured by HPLC-ESI-MS/MS of the Derivatives Taurultame and Taurinamide in Glioblastoma Patients

Stendel, Ruediger; Scheurer, Louis; Schlatterer, Kathrin; Stalder, Urs; Pfirrmann, R. W.; Fiss, Ingo; Möhler, Hanns; Bigler, Laurent

doi:10.2165/00003088-200746060-00005

Cited by 27 publications

(26 citation statements)

References 16 publications

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“…The anti-neoplastic activity of the parent compound TRD has been demonstrated in many studies on different cancer entities in vitro as well as in vivo [18, 20, 21] . Even pilot clinical studies confirmed previous results [16, 18, 22]. Therefore, the aim of this study was to analyze anti-neoplastic effects of substance 2250 in comparison to its structural analogue TRLT, the main derivative of its effective parent compound TRD.…”

Section: Discussionsupporting

confidence: 68%

Innovative substance 2250 as a highly promising anti-neoplastic agent in malignant pancreatic carcinoma - in vitro and in vivo

et al. 2017

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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.

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Section: Discussionsupporting

confidence: 68%

Innovative substance 2250 as a highly promising anti-neoplastic agent in malignant pancreatic carcinoma - in vitro and in vivo

et al. 2017

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“…Taurolidine further triggered cell shrinkage, another hallmark of eryptosis [58]. The concentration required for stimulation of eryptosis was similar to those required to trigger apoptosis of tumor cells [114][115][116][117] and to those achieved in patients [118].…”

Section: Discussionmentioning

confidence: 69%

Taurolidine Sensitivity of Eryptosis, the Suicidal Erythrocyte Death

Fink

Bhuyan

Zacharopoulou

et al. 2018

Cell Physiol Biochem

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Background/Aims: The taurine derivative Taurolidine is effective against diverse bacteria and tumor growth. In the treatment of cancer, the substance is effective in part by triggering suicidal death or apoptosis of tumor cells. The Taurolidine-induced apoptosis involves mitochondria. Erythrocytes lack mitochondria but are nevertheless able to enter suicidal erythrocyte death or eryptosis, which is characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Signaling of eryptosis includes increase of cytosolic Ca²⁺ activity ([Ca²⁺]_i), oxidative stress and ceramide. The present study explores, whether Taurolidine induces eryptosis and, if so, which cellular mechanisms are involved. Methods: Phosphatidylserine exposure at the cell surface was estimated using annexin-V-binding, cell volume using forward scatter, [Ca²⁺]_i using Fluo3-fuorescence, reactive oxygen species (ROS) formation using 2’,7’-dichlorodihydrofuorescein (DCF)-dependent fluorescence, and ceramide abundance using specific antibodies. Results: A 48 hours exposure of human erythrocytes to Taurolidine (60 µg/ml) significantly enhanced the percentage of annexin-V-binding cells, significantly decreased forward scatter and significantly increased Fluo3-fluorescence and ceramide abundance, but not DCF-fluorescence. The effect of Taurolidine on annexin-V-binding was virtually abrogated by removal of extracellular Ca²⁺. Conclusion: Taurolidine triggers cell shrinkage and phospholipid scrambling of the erythrocyte cell membrane, an effect at least in part due to Ca²⁺ entry and paralleled by increase of ceramide abundance.

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“…52 The pharmacokinetic profile of TAU permits therapeutic use, leading to mean plasma concentrations of TAU of 83 ± 18.1 μg/ml during intravenous application in humans. 53 This value compares favorably to the facts that TAU at very low concentrations leads to a dramatic reduction or even prevention of proliferation (from ca. 2 μg/ml) and inhibition or prevention of colony formation (EC 50 = 1.2 ± 0.6 μg/ml), and at higher concentrations to acute cell killing (EC 50 = 71.2 ± 19.6 μg/ml).…”

Section: Methodsmentioning

confidence: 70%

The antibacterial substance taurolidine exhibits anti-neoplastic action based on a mixed type of programmed cell death

Stendel¹,

Biefer²,

Dékány³

et al. 2009

Autophagy

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The antibacterial amino-acid derivative taurolidine (TAU) has been recently shown to exhibit anti-neoplastic activity based on a mechanism, which is still unknown in detail. Cytotoxicity and clonogenic assays were performed and the impact of apoptosis modulators, a radical scavenger, autophagy inhibitors, silencing of apoptosis inducing actor (AIF) and cytochrome-c (Cyt-C) by siRNA, and knockdown of autophagy related genes were evaluated in vitro. The intracellular ATP-content, release of AIF and Cyt-C, and DNA-laddering were investigated. This study could demonstrate cell killing, inhibition of proliferation, and inhibition or prevention of colony formation in human glioma cell lines and ex vivo glioblastoma cells after incubation with TAU. This effect is based on the induction of a mixed type of programmed cell death with the main preference of autophagy, and involvement of senescence, necroptosis and necrosis. This mechanism of action may open a new approach for therapeutic intervention.

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Pharmacokinetics of Taurolidine following Repeated Intravenous Infusions Measured by HPLC-ESI-MS/MS of the Derivatives Taurultame and Taurinamide in Glioblastoma Patients

Cited by 27 publications

References 16 publications

Innovative substance 2250 as a highly promising anti-neoplastic agent in malignant pancreatic carcinoma - in vitro and in vivo

Innovative substance 2250 as a highly promising anti-neoplastic agent in malignant pancreatic carcinoma - in vitro and in vivo

Taurolidine Sensitivity of Eryptosis, the Suicidal Erythrocyte Death

The antibacterial substance taurolidine exhibits anti-neoplastic action based on a mixed type of programmed cell death

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