Taurolidine: A Disinfectant & Inhibitor of Tumor Growth

Background:

Taurolidine is a molecule that comprises Taurine (the most abundant free amino acid in the heart, retina, skeletal muscle, brain, and leukocytes). It was first produced in the 1970s by Geistlich-Pharma Inc, designed as a broad-spectrum antibiotic and used in the local treatment of peritonitis. (Ref.) It is effective against both aerobic and anaerobic bacteria. (Ref.) Due to its antibacterial and anti-toxin (exo/endotoxin) activity it was tested clinically in the 1980’s in the treatment of severe surgical infections and abdominal sepsis (Ref.).

It is currently used in several European countries for the treatment of peritonitis under the name Taurolin (Ref.1, Ref.2). It is nontoxic and has an excellent safety record since its initial introduction (Ref.).

Since 1990’s multiple patents have been filed by Geistlich-Pharma and others on Taurolidine as a potential treatment of cancer alone or in combination with other drugs (Ref.1, Ref.2, Ref.3, Ref.4, Ref.5). More patents on this line can be found here: https://www.google.com/search?tbm=pts&hl=en&q=taurolidine+cancer

In parallel to the patent writing by the industry, scientists have demonstrated in the lab the effectiveness of Taurolidine against cell lines such as:

Following the very promising results discussed above, Taurolidine has been first time applied in humans in 2004 on two glioblastoma patients at Free University of Berlin and reported in the following paper http://ar.iiarjournals.org/content/24/2C/1143.full.pdf. Taurolidine was administered via intravenous route each day during several weeks and that led to partial regression of the tumors in both patients that were joining the study. There was no toxicity observed following Taurolidine application. Unfortunately, such innovative treatments are only applied when the tumors are very advanced and typically patients are in very bad shape due to prior treatments.

Since 2004, Taurolidine has been used constantly to treat cancer patients in various private clinics in Germany. As discussed below, there is another published case report from Berlin, in 2006, regarding a gastric cancer patient who following Taurolidine treatment survived several years and had a complete remission. However, the doctors didn’t not know the tumor is death and latter tried to perform a surgery to remove the tumor. The surgery was lethal for the patient.

I do know a lady with ovarian cancer and multiple metastais, who responded well and became nearly clean of tumors after Taurolidine treatments at a clinic in Germany, while another patient I know did not responded.

One of the doctors most experience with Taurolidine seems to be Prof. Jacobi, Wesseling, Germany (at http://www.krankenhaus-wesseling.de) https://www.researchgate.net/profile/Christoph_Jacobi3, a surgeon specialized in stomach and colorectal cancer. However, there are more places with experience in using Taurolidine in Germany.

Interestingly, Taurolidine has also shown great results in treating Papillomatosis in animals (Ref.).

Case reports in humans:

Treatment of Glioblastoma with Intravenous Taurolidine. First Clinical Experience http://ar.iiarjournals.org/content/24/2C/1143.full.pdf

In a clinical experience with two patients with progressive, non-resectable glioblastoma and conventional therapy, the neurological condition and the quality of life improved in both patients with no sign of tumor progression (‘partial remission’) following two cycles of 21 days each with 2% Taurolidine i.v. (20 g/day). Unfortunately, the patients passed away several months latter due to complications from their tumor in one patient, and medication that was previously administered for the other patient.

Prevention of disease progression in a patient with a gastric cancer-re-recurrence. Outcome after intravenous treatment with the novel antineoplastic agent taurolidine. Report of a case https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1544327/

A patient with gastric cancer re-recurrence was palliatively treated with 2% Taurolidine i.v. for 39 cycles, each cycle consisting of 7 days of treatment per month (300 mg/kg body weight per day). The patient endured the therapy well and no toxicity was observed. CT-scans revealed a stable disease without a tumor progression or metastatic spread.

Four weeks after the completion of the treatment the patient was admitted to the urology department of the hospital in order to perform a surgical treatment of his urothelial carcinoma. A left nephrectomy was performed. Although there were no intraoperative problems the patient unexpectedly died of an acute myocardial infarct 48 hours as a complication to the surgery.

In their article, the authors write: “Post mortem histology of the esophageal-jejunal anastomosis and liver revealed surprisingly no signs of the known adenocarcinoma. We thought this finding was extremely interesting as we had actually been in front of a complete remission of his gastrointestinal tumor.”

Mechanism:

The anti-infective agent Taurolidine (TRD) has been shown to have cell death inducing properties, but the mechanism of its action is largely unknown. http://www.ncbi.nlm.nih.gov/pubmed/21034493

However, there is growing evidence from recent publications, that generation of reactive oxygen species (ROS) plays an important role in TRD induced programmed cell death (PCD) http://www.ncbi.nlm.nih.gov/pubmed/20205945. Indeed, strong antioxidants such as NAC has been shown to block or strongly reduce the cytotoxicity of Taurolidine in nearly all tumor cells (Ref.).

Taurolidine seems to also inhibit angiogenesis (Ref.) and suppress VEGF production (Ref.)

Taurolidine upregulated the NFκB inhibitor NFκBIA (Ref.) NFκB also regulates the release of the proinflammatory mediators IL-1, IL-6 and TNFα. Indeed, Taurolidine is known as an anti inflammatory drug protecting animals against endotoxic shock and death, and blocking tumor necrosis factor (TNF) and interleukin 1 (IL-1) synthesis (Ref.).

Given that Taurolidine is a pro-oxidant, it should work well with all other proxidant theraphies such as chemo, DCA, Vitamin C, 3BP, Artemisinin.

Safety:

For use in the blood stream the drug has demonstrated high safe margin and it has several properties which suggests it can be useful in cancer treatment: “A remarkable experimental observation that comes to complete the above-mentioned findings is the low toxicity on leukopoiesis and erythropoiesis as well as on kidney and liver function in animal models.” (Ref.)

Here is a PhD thesis from Berlin 2008, where they do not recommend the compound for treatment of Bladder cancer as it may enhance the tumor growth: http://www.diss.fu-berlin.de/diss/receive/FUDISS_thesis_000000003780?lang=en

Pharmacokinetics:

The pharmacokinetic profiles of taurolidine metabolites was first established in a study including 18 healthy volunteers who received 5.0 g of taurolidine in 250 mL of 5% polyvinylpyrrolidone in water over 2, 1, or 0.5 hours by intravenous infusion in a parallel-group design. (Ref.)

The average patient plasma concentration of taurolidine following IV administration was found to be 83.0 µg/mL that is within the anti-neoplastic effective concentration range determined in vitro (Ref.).

Credit figure: http://www.zora.uzh.ch/20797/2/Habil_UniZH_Bigler.pdf Note: in this case each every two hours 5g Thalidomide has been administered with an hour break, that is a total of 20g each day.

Source:

A commercial preparation of taurolidine for intravenous infusion is available as a 2% solution (Taurolin®) in 100ml and 250ml version and as a 0.5% solution in 500ml version. Here is an example of that  http://www.devrimed.nl/taurolin.php

In Europe, Taurolidine is available at pharmacy (Ref.) but it is relatively expensive given that 10x250ml bottles cost 485 euro. If it is to follow some of the intensive treatment strategy discussed below, this would be enough for 2.5 days. However, lower daily dose may also be tried, since according to the pharmacokinetics from above two bottles / day may also be enough to reach the anti cancer plasma level for several hours.

In the Netherlands, with prescription, it seems to be available for free at some pharmacies.

Application:

Taurolidine can be administered intravenous (i.v.) or intraperitoneal (i.p.). Taurolidine irrigation is also used sometimes during laparoscopy to reduce chance of metastasis https://www.ncbi.nlm.nih.gov/pubmed/15744592 https://www.ncbi.nlm.nih.gov/pubmed/11735264

Here I will focus on the IV application. There are several sources of information on its application, each suggesting a slightly different treatment strategy:

    • Four bottles (250 ml each) of 2% taurolidine solution
    • One bottle every six hours (2 hours, followed by a four hour break)
    • The therapy cycle generally is an administration phase of daily infusions for one week, followed by a rest phase of two weeks
    • Total treatment generally is at least two such cycles
    • Efficacy of taurolidine 2% solution administered intravenously has been found to be particularly good with 25-28 bottles of 250 ml taurolidine 2% solution being instilled per cycle
      Reference: http://www.google.ch/patents/CA2379734C?hl=de&cl=en and http://ar.iiarjournals.org/content/24/2C/1143.full.pdf
      Disadvantage is that this schedule implies treatment trough the night.
      .
    • Four bottles (250 ml each) of 2% taurolidine solution
    • One bottle every six hours (2 hours, followed by a four hour break)
    • The therapy cycle generally is an administration phase of daily infusions for two days, followed by a rest phase of five days
    • Continue until remission
      Reference: some german clinics
      Disadvantage is that this schedule implies treatment trough the night
      .
    • Four bottles (250 ml each) of 2% taurolidine solution
    • One bottle every 3 hours (2 hours, followed by one hour break)
    • This during 21 days as one cycle
    • A break of a few weeks followed by another cycle
      Reference: (Stendel et al. 2002; Stendel et al. 2004). http://www.zora.uzh.ch/20797/2/Habil_UniZH_Bigler.pdf
      Advantage is that this schedule dose not go trough the night
      .
    • Two bottles (250 ml each) of 2% taurolidine solution
    • One bottle every 3 hours (2 hours, followed by one hour break)
    • Two days/week
    • Done until cancer free
      Reference: this is my idea based on the pharmacokinetics data. This dose should reach the anticancer plasma level and would be relatively double as it is six hours/day and two days/week. The cost should also be OK, given that 2 bottles will cost 100 euro.
      .
    • Prof Dr Jacobi seems to also suggest in one of his book as the best protocol being also one bottle of Taurolidine 2% (250ml) every day during 21 days (he uses also Interleukin2 in a combination).
      .
    • Four bottles (250 ml each) of 2% taurolidine solution – aim to use 300 mg/kg/day in total
    • One bottle every six hours (2 hours, followed by a four hour break)
    • The therapy cycle generally is an administration phase of daily infusions for 5 days
    • Each month one of such cycle is applied
      Reference: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1544327/

Taurolidine is very alkaline and needs to be given through a port-a-catch.

Besides the IV application, the perioperative use of Taurolidine solution (2%) in surgical oncology promises to be of special benefit as it is administered at the earliest possible therapeutic time window. Perioperatively, circulating tumor cells, which correlate negatively with disease free survival and overall survival, would be the prime targets for Taurolidine. By its ability to be cytotoxic to tumor cells and tumor stem cells, perioperative Taurolidine promises to reduce micrometastases and increase survival, as substantiated in a pancreatic cancer model (Ref.).

Clinics using Taurolidine:

Dr.med.Bozena Kilarski, Schumannstr 48, D-48431 Rheine, Germany
Tel +495971 984 606, Fax.+495971 984607, www.dr-med-Kilarski.de, Mail : [email protected]

Prof. Dr. med. Christoph Andreas Jacobi, http://www.krankenhaus-wesseling.de/medizinische-bereiche/medizinische-fachabteilungen/chirurgie/
Bonner Straße 8450389 Wesseling Nordrhein-Westfalen Germany
Telefon: 02236/77-276
Mail: [email protected]

References:

Treatment of glioblastoma with intravenous taurolidine. First clinical experience. https://www.ncbi.nlm.nih.gov/pubmed/15154639

BACKGROUND: Despite progress in diagnosis and therapy, the prognosis of patients with glioblastoma remains poor. Recently it has been found that the antibacterial agent taurolidine has a direct and selective antineoplastic effect on brain tumor cells by the induction of programmed cell death. This paper reports on intravenous taurolidine treatment in two patients with a progressive glioblastoma despite conventional therapy. PATIENTS AND METHODS: Two male patients with histopathologically diagnosed glioblastoma were included. The tumors were progressive despite conventional therapy. Intravenous taurolidine treatment was initiated. RESULTS: The neurological condition and quality of life improved in both patients such that they could be discharged for further outpatient treatment. Follow-up demonstrated partial remission of the tumor in both patients. However, both patients died about 4 months following the start of taurolidine treatment, from pneumonia and acute thrombembolism, respectively. CONCLUSION: Both patients achieved a transient, marked improvement in quality of life and partial tumor remission. There was a clear response to the taurolidine treatment.

Taurolidine: cytotoxic and mechanistic evaluation of a novel antineoplastic agent. https://www.ncbi.nlm.nih.gov/pubmed/11559556

Bis-(1,1-dioxoperhydro-1,2,4-thiadiazinyl-4)methane (taurolidine) is a synthetic broad-spectrum antibiotic that reacts with bacterial cell membrane components to prevent adhesion to epithelial cell surfaces. Reflecting the key role of adhesion in the growth and development of human solid tumors, studies were initiated to assess the antiproliferative activity of this agent in selected human and murine tumor cell lines. A 3-day exposure to Taurolidine inhibited the growth of all of the cell lines evaluated with IC(50)s ranging from 9.6-34.2 microM. Studies to identify the mechanism responsible for this effect were conducted in NIH-3T3 murine fibroblasts and the PA-1 and SKOV-3 human ovarian tumor cells. These studies revealed that a 48-h exposure to taurolidine had little effect on cell cycle distribution in PA-1 and SKOV-3 cells but significantly increased the appearance of DNA debris in the sub-G(0)/G(1) region, an effect consistent with an induction of apoptosis. In contrast, in NIH-3T3 cells, taurolidine exposure did not increase DNA debris in the sub-G(0)/G(1) region. Additional studies assessed phosphotidylserine externalization after a 24-h exposure to taurolidine using annexin-V binding as a cell surface marker. These studies revealed that taurolidine increased the percentage of annexin-V-positive cells by 4-fold and 3-fold in PA-1 and SKOV-3 cells, respectively. In NIH-3T3 cells, taurolidine exposure slightly increased ( approximately 5%) annexin-V binding. Parallel studies revealed that exposure to taurolidine also resulted in poly(ADP-ribose) polymerase cleavage in both ovarian tumor cell lines but not in NIH-3T3 cells. Finally, murine-based studies were conducted to assess the antineoplastic activity of three consecutive daily i.p. bolus injections of taurolidine at doses ranging from 5-mg injection/mouse to 30-mg injection/mouse. The 20-mg injection dose produced approximately 10% mortality and was identified as the maximally tolerated dose in this model. Administration of this regimen to nude mice bearing i.p. human ovarian tumor xenografts significantly inhibited both tumor formation and growth. These findings are discussed in light of their clinical implications.

Enhancement of Fas-ligand-mediated programmed cell death by taurolidine. https://www.ncbi.nlm.nih.gov/pubmed/12894508

The antineoplastic activity of taurolidine seems to be partially based on the enhancement of Fas-ligand-induced apoptosis. In addition, taurolidine was demonstrated to have an antieoplastic effect independent of Fas-ligand. Perhaps taurolidine exerts antineoplastic activity based on different mechanisms.

The evolving role of taurolidine in cancer therapy. https://www.ncbi.nlm.nih.gov/pubmed/20039217

BACKGROUND AND DESIGN: Taurolidine consists of two taurinamide rings derived from the naturally occurring amino acid taurine. It has been utilized to prevent adhesions, as an antimicrobial, and as an anti-inflammatory agent. More recently, it has been found to exert antineoplastic activity. We reviewed the literature regarding taurolidine and its role in cancer treatment. RESULTS AND CONCLUSION: 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.

Redox-directed cancer therapeutics: Taurolidine and Piperlongumine as broadly effective antineoplastic agents (review)https://www.ncbi.nlm.nih.gov/pubmed/25175943

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.

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22 Comments on "Taurolidine: A Disinfectant & Inhibitor of Tumor Growth"

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wonderwoman
Member

hi daniel! long time , apologies for my long abscence in communcation. Still fighting the demon. im considering this treatment for my mom. who would be worth contacting based on the two contacts given? What could the potential risks be?

bumped into the following:

https://www.ncbi.nlm.nih.gov/pubmed/22120774

had me a bit worried.Would love to pick your brain.

ALBERTO
Guest
Hi Daniel, after doing some research, I think is worth to try this therapy. I highly recommend to spend a few euros and do a test of sensitivity for example with Maintrac, then you can get a better idea which substances are more effective against the tumor. The only thing I disagree is about the route of administration, obviously is better if you have a central line but you can also give peripherally. And a very important think to highlight is dont give with Vitamin C. I am going to suggest to one of my patients with a very advance… Read more »
Wondering
Guest

hi Alberto, im no doctor but i understand vitamine c is avoidable with almost each chemotherapy, related to ROS levels maybe?

Alberto
Guest
Today we are starting the first cycle of taurolidine. A bit nervous. I finally decided to put a central line. Due to low tonicity I will also give plasmalyte during infusion. After research I have decided to do my own protocol, 2 weeks treatment ,(5 days + 2 break) x 2, then 1 week break and repeat the cycle. In totally i will give 60 bottles (300 mg/kg/d). 2 h taurolidine + 1 h break x 3 times a day. We did a Maintrac test last week so we can monitor the response better. I will keep you update. I… Read more »
Alberto
Guest

First cycle of Taurolodine finished
We did 300mg/kg/d, for 14 days with 2 days break in the middle, now one week off, we will do Ca125 and assess if any response has occurred. Then we will do another cycle and after, another Maintrac test to see the response it was not any side effects. I have added heparin iv most of the days. I will post the markers soon.

Hectoria
Guest

Hi Alberto, may I ask how you are getting on with your ovarian patient? If it is working well, perhaps I can come to see you as your patient. I am looking for an alternative to chemo.
Thanks

hectoria
Guest

Hi Daniel, Can you tell me the name of the clinic used by the ovarian cancer patient you mentioned who was nearly cleared of her mets by Taurolidene? I think I might give it a go if you think it worthwhile. I have quite a lot of mets, in my spleen, pelvis and lymp nodes. That was the state of play in February, but am scheduled for another scan next week. Am very anxious it has spread in the last three months.
Thanks,

ALBERTO
Guest

Hi Guys, just an update about our treatment with Taurolodine, we finished the 2nd cycle of Taurolodine. In totally we gave 70 bottles of 2%, so 350 grams. No side effects. First Ca125 dropping so good news but still not normalized. May be to early to see the effect but better dropping than rising. Another patient, in this case with brain tumor is going to start with iv Taurolodine, I will keep ypu update

Hectoria
Guest

This is very encouraging news re taurolidine. May I ask how much the CA 125 came down as a result? I am probably stopping Taxol due to bowel complications, and would be interested in trying the taurolidine further down the line.

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