In vivo Evaluation antiproliferativ-antiangiogener Therapiestrategien beim anaplastischen Schilddrüsenkarzinom

Das Schilddrüsenkarzinom ist die häufigste endokrine Tumorentität mit einer Inzidenz von 4,3 / 100.000 Erkrankungen pro Jahr bei Männern und 9,9 / 100.000 bei Frauen (Stand 2012). Unter den verschiedenen Schilddrüsenkarzinomentitäten hat das anaplastische Karzinom die höchste Mortalität. Eine kausal...

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Bibliographic Details
Main Author: Josephs, Dennis
Contributors: Hoffmann, Sebastian (Prof. Dr.) (Thesis advisor)
Format: Dissertation
Language:German
Published: Philipps-Universität Marburg 2015
Operative Medizin
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Table of Contents: Thyroid carcinoma is the most frequent endocrine neoplasma with an incidence of 4.3/100.000 cases in male and 9.9/100.000 in female patients (2012). Among the variety of thyroid cancers the anaplastic carcinoma is associated with the highest mortality rate. A causative surgical therapy is not effective in most cases and therefore an alternative multimodal therapeutic concept based on new compounds is an additional option. This study investigates three inhibitors of the enzyme thyrokinase (AEE788, gefitinib and vandetanib) and a monoclonal antibody (cetuximab). Previous studies could demonstrate that EGF (endothelial growth factor) and VEGF (vascular endothelial growth factor) secretion was significantly reduced by tyrokinase inhibitors. Hence, this results in decreased proliferation and angiogenesis. An anaplastic cell line (Kat 4) was xenotransplantated in nude mice (NU/Nu...). Tumor groth was evaluated after seven days and the mice randomised in single groups. AEE788, gefitinib and vandetanib were given enterally via a nasogastric tube. Cetuximab was injected intraperitoneally. Application of compounds followed a standardised schedule. Mice were weighed weekly and the size of the tumor was measured. After 4 - 5 weks the mice were sacrificed and the tumor surgically removed. Probes of the tumor were embedded in paraffine and we prepared slices that were stained immunohistochemically with bromuridine. Since this stain only aggregates in proliferating cells we could analyse the division of cells in the tumor. With CD31 staining we were able to demonstrate tumor vessel proliferation. Applying the Barth formula we determined vessel surface in relationship to tumor volume and vessel density. In this study we could demonstrate a significant reduction of tumor proliferation rate by the above mentioned compounds. A combination therapy of AEE788 with gefitinib and vandetanib resulted in a sound reduction of tumor mass. A similar result was achieved for the reduction of vessel surface per tumor volume. The combination therapy and the single treatment with cetuximab resulted in significant reduction of vessel density. Concerning the minimisation of the vessel number the combination therapy of gefitinib and vandetanib was superior compared to single application of cetuximab. These results demonstrate a good correlation with other international trials. In several other tumorentities a similar success in tumor reduction was achieved with AEE788, gefitinib, vandetanib and cetuximab. Hence, some of these compounds have become standard in chemotherapy. In future a multimodal therapy like a combination of radiation, surgical debulking and chemotherapy with some of the new compounds seems a promising alternative option for the treatment of patients with anaplastic thyroid carcinoma.