Peritumorale Entzündung, chronische Pankreatitis und Chemoresistenz von Gemcitabin bei der Therapie des Pankreaskarzinoms – Evaluation am transgenen Tumormausmodell

Patienten mit metastasiertem Pankreaskarzinom, die erhöhte CRP-Werte aufwei-sen, profitierten kaum von einer Gemcitabintherapie (Nakachi et al., 2007). Die Zusammenhänge von systemischer Inflammation, chronischer Pankreatitis und Chemotherapieversagen sind bisher unklar. Um den Einfluss einer milden...

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Bibliographic Details
Main Author: Knoop, Richard F.
Contributors: Fendrich, Volker (Prof. Dr. med.) (Thesis advisor)
Format: Doctoral Thesis
Published: Philipps-Universität Marburg 2014
Online Access:PDF Full Text
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BACKGROUND AND AIMS: Gemcitabine is the standard therapy for patients with pancreatic cancer with metastatic disease. Patients with metastatic pancreatic cancer presenting with increased values of C-reactive protein do not respond to gemcitabine. So far, no studies have evaluated the correlation between chronic pancreatitis, systemic inflammatory response syndrome, and the loss of chemotherapeutic benefit. METHODS: Pdx-1-Cre;LSL-KrasG12D/+;LSL-Trp53R172H/+ mice were assigned into four groups: 1) Sixteen animals received a daily intraperitoneal injection of caerulein from their ninth week of life on. 2) Sixteen mice were additionally given gemcitabine. 3) Twelve animals received gemcitabine only. 4) Saline-treated control group. Furthermore, human Paca44 pancreatic ductal adenocarcinoma cells were seeded and cultured in 0.5% FBS containing growth medium plus/minus 1 μM gemcitabine plus/minus recombinant human interleukin (IL)-6. RESULTS: Induced systemic inflammatory response syndrome and a mild chronic pancreatitis diminished the beneficial effects of gemcitabine upon median overall survival. In median, the monogemcitabine group survived 191 days, whereas the caerulein-mono group survived 114, the control group 121, and the caerulein gemcitabine group 127 days (P < .05). In vitro, the induction of STAT3 phosphorylation by recombinant human IL-6 promoted pancreatic ductal adenocarcinoma cell survival during gemcitabine treatment. CONCLUSION: We could demonstrate for the first time that an improvement in median overall survival with gemcitabine is significantly abolished by a persistent mild chronic pancreatitis and a systemic inflammatory response syndrome. In particular, the inflammation biomarkers C-reactive protein, IL-6, and IL-1α could indicate the prognostic benefit of gemcitabine chemotherapy and should now be tested in prospective patient-controlled trials.