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| Antineoplastische und antiangiogene Effekte von Taurolidin -
vom molekularbiologischen Experiment zum klinischen Einsatz Braumann, Chris |
| Main title | Antineoplastische und antiangiogene Effekte von Taurolidin - vom molekularbiologischen Experiment zum klinischen Einsatz |
| Title variations | Antineoplastic and antiangiogenic effects of taurolidine - molecular experiments and clinical use |
| Author(s) | Braumann, Chris
Place of birth: Torgau |
| 1. Referee | Prof. Dr. C.-D. Heidecke/Greifswald |
| Further Referee(s) | Prof. Dr. E. A. M. Neugebauer/Köln |
| Classification (DDC) | 610 Medical sciences; Medicine |
| Summary | Taurolidine (TRD) is an agent with antiseptic and antineoplastic effects clinically first administered in 1975. It is a soluble product of the amino acid Taurin and is hydrolytically separated to its active metabolites Taurultam and Methyltaurultam. Its contact with bacteria leads to loss of their pathogenesis. TRD inhibits the release of TNFα and IL-1β as well as angiogenesis, which is of great importance for solid tumor growth. The mechanisms of TRD antineoplastic effects were investigated. TRD has an antineoplastic effect on more than 30 cell lineages in vitro. We have thoroughly examined its molecular mechanisms of action. Experiments showed a reduction of the intracellular protein level of transcription factors and cell cycle regulators. Effects on the COP9 signalosome, a multimeric regulatory protein complex involved in signal transduction and ubiquitin-dependent proteolysis could be excluded. The Transcription process was not blocked by the highest TRD concentrations. The translation was intensively assessed by sucrose density gradient centrifugation. It was shown that TRD acts as an inhibitor of an early phase in translation. It blocks protein biosynthesis in mammalian cells as well as in bacteria, which mig ht explain most of its pleiotropia effects, including induction of apoptosis. Antineoplastic effects of TRD were confirmed in several experimental studies on animal models. A single intraperitoneal (IP) dose caused a reduction of intra- and extraperitoneal metastases in rats. Direct contact with tumor cells had a much higher antineoplastic effect than the single intravenous (IV) application after laparoscopy or laparotomy. Further experiments showed that longer IV administration with higher doses could inhibit IP tumor growth and subcutaneous metastatic disease without relevant toxic effects in rats. The IP and IV administration of TRD reduced total tumor weight and number of metastatic lesions of disseminated malignant melanoma in a dose dependent way in mice. Our encouraging findings will be further examined in clinical studies. The effect of intraoperative IP instillation of TRD versus PVD-iodine in colorectal, gastric and pancreatic cancer was examined in a multicenter prospective randomized clinical trial. Lavage with TRD delayed the increase of IL-1β compared to the control group without relevant adverse effects. As a result the IP administration TRD could be of benefit as a treatment for the prevention of metastasis in surgical oncology. Therefore, a new prospective randomized multicenter trial was set up in November 2005. Aim of this study was to examine the influence of intraoperative instillation and abdominal lavage with 2% TRD versus irrigation with 0.9% NaCl (control group) on metastases and local tumor recurrence (n=2000). A significant advantage of TRD is the absence of adverse effects on haemopoiesis. TRD 2 % is being currently applied intravenously as part of a Phase III clinical study, in order to assess safety and toxicity of the agent in patients with advanced or recurrent gastric and pancreatic cancer. The bodyweight correlated TRD doses of 300 mg/kg KG/Day had nor clinical neither biochemical adverse effects. In some patients with recurrence of gastric cancer we observed a slow progression of the disease with a good quality of life. In one patient no evidence of his previous gastric cancer re-recurrence was detected. Summarizing, the combination of antineoplastic effects of TRD with a low toxicity render the substance a promising therapeutic option for several malignancies, where traditional therapeutic modalities fail. TRD could be administered either as monotherapy or as part of a protocol with other chemotherapeutics in the future. |
| Content | 1. Zusammenfassung 3 2. Einleitung 5 3. Verzeichnis der zur kumulativen Habilitationsschrift zusammengefassten Anlagen 7 4. Studienergebnisse 8 4.1. Antineoplastische Effekte von Taurolidin und Heparin bei der offenen Behandlung eines disseminierten Kolonkarzinoms. Ein Rattenmodell 8 4.2. Tumorwachstum nach Behandlung mit Taurolidin und Heparin unter den Bedingungen eines Pneumoperitoneums mit Kohlendioxid bei der Ratte 17 4.3. Dosissteigerung bei Bolusinjektion oder Langzeitbehandlung mit Taurolidin auf das Tumorwachstum. Ein Rattenmodell 24 4.4. Hohe Taurolidindosen inhibieren fortgeschrittenes Tumorwachstum. Ein Rattenexperiment 32 4.5. Taurolidin blockiert die Proteinbiosynthese 40 4.6 Taurolidin inhibiert das Wachstum eines malignen Melanoms. Ein Mausmodell. 47 4.7. Intravenöse Behandlung mit Taurolidin – Progressprävention bei einem Magenkarzinom-Re-Rezidiv. Eine Falldarstellung. 55 5. Diskussion 62 5.1. Molekularbiologische Untersuchungen 62 5.1.1. Angiogenese und Inhibitionsmöglichkeiten 62 5.1.2. Analyse neuer taurolidinähnlicher Substanzen 63 5.1.3. In silico screening zur Detektierung von Angiogenesehemmstoffen 63 5.1.4. In vitro Untersuchungen mit neuen Antiangiogenetika 65 5.2. Tierexperimentelle Forschungen 66 5.3. Klinischer Einsatz unter Studienbedingungen 71 6. Abkürzungsverzeichnis 77 7. Literaturverzeichnis 78 8. Eidesstattliche Erklärung 90 |
| Documents |
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| Number of pages | 90 |
| FU Department | Department of Medicine - Charité - University Medicine Berlin |
| Year of publication | 2008 |
| Document type | Habilitation treatise |
| Media type/Format | Text |
| Language | German |
| Terms of use/Rights | Nutzungsbedingungen |
| Date of defense | 2008-12-08 |
| Created at | 2009-03-24 : 10:29:26 |
| Last changed | 2010-02-19 : 11:03:35 |
| Static URL | http://www.diss.fu-berlin.de/diss/receive/FUDISS_thesis_000000009167 |
| NBN | urn:nbn:de:kobv:188-fudissthesis000000009167-4 |
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