Untersuchungen zur Chemo- und Radiosensitivität und deren Auswirkungen auf Zellzyklus, Apoptoseinduktion und Genexpression in neuroendokrinen Pankreastumorzellen

Die zur Behandlung maligner neuroendokriner gastroenteropankreatischer Tumoren eingesetzten Chemotherapeutika führen bisher zu keiner deutlich verbesserten Überlebenszeit der Patienten. Vor diesem Hintergrund sollte in vitro die Chemosensitivität bzw. Chemoresistenz der neuroendokrinen Pankreastumor...

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Bibliographic Details
Main Author: Robbel, Christian
Contributors: Simon, Babette (Prof. Dr. med.) (Thesis advisor)
Format: Doctoral Thesis
Language:German
Published: Philipps-Universität Marburg 2005
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Table of Contents: Treatment of patients with dissiminated functional pancreatic endocrine tumors is palliative. It includes the use of biotherapeutics, as well as application of chemotherapy to relieve symptoms and to reduce tumor volume. At present, the combination of streptozotocin and doxorubicin is the regimen of choice. In rapidly growing anaplastic small cell neuroendocrine tumors, the combination of cisplatin and etoposide seems to be more effective. However, response to chemotherapy and survival benefit is limited and often impaired by substantial side effects. In order to identify potential more effective agents in neuroendocrine pancreatic tumors in this study, the endocrine pancreatic tumor cell line BON I was treated with different conventional chemotherapeutic agents and cell cycle perturbation, induction of apoptosis and gene and protein expression were assessed. It was shown that paclitaxel elicts a strong antiproliferative effect with an early time and dose-dependent induction of G2/M arrest and concomitant induction of apoptosis. Furthermore, a slight radiosensitizing effect of paclitaxel was observed, though being limited to a defined drug and radiation dose level. Gen expression analysis with RT-PCR and cDNA arrays revealed upregulation of several cyclins, cdk’s, cdki’s and different cell-cycle and apoptosis related genes after 48h of treatment. Although a few p53-associated genes were overexpressed, there was no indication of p53 transcription-dependent cell death. Also, no evidence for death receptor-mediated apoptosis was found. Despite a strong G2/M arrest was also shown with some of the other drugs, no other agent used had such a marked induction of apoptosis at any of the examined time and dose intervals than paclitaxel. In respect to the obtained in vitro findings, a superior antiproliferative effect of paclitaxel may also be conceivable in vivo and should be addressed in clinical studies.