Enalapril als Chemoprävention des duktalen Pankreaskarzinoms im transgenen Tumormausmodell

In Deutschland erkranken jährlich etwa 12.600 Menschen am duktalen Adeno-karzinom des Pankreas, was 3 Prozent aller Krebserkrankungen entspricht (1). Die Gründe für die schlechte Prognose liegen in der späten Diagnosestellung und der aggressiven Tumorzellbiologie. Nur 10 bis 20 Prozent der Patienten...

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Bibliographic Details
Main Author: Chen, Nai-Ming
Contributors: Fendrich, Volker (Dr.) (Thesis advisor)
Format: Doctoral Thesis
Language:German
Published: Philipps-Universität Marburg 2012
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Table of Contents: Pancreatic cancer is a devastating and almost uniformly lethal malignancy that accounts for approximately 12,600 deaths in Germany every year (1), 3 Percent of all cancers. The reasons for the poor prognosis are too late to diagnose and the aggressive biology of the tumor cell. At the time of diagnosis, pancreatic cancer is usually at an advanced stage and has often metastasis. Only 10 to 20 percent of patients have a resectable tumor. But less than 2 percent of patients survive five years. For patients with the resectable primary tumor is the median survival 10 to 12 months. Patients with adjuvant chemotherapy may survive up to 20 months (51). An advanced tumour stage come only palliative measures. Survival without therapy is around 3 to 4 months (22). The results of chemotherapy, adjuvant radio and Intraoperative irradiation are not satisfactory. Notably, there is now strong evidence that invasive pancreatic adenocarcinoma proceeds through a morphological spectrum of non-invasive ductal lesions known as pancreatic intraepithelial neoplasia (PanIN), David A. Tuveson showed that the transgenic mice had the similar dysplasia-carcinoma sequence of pancreatic cancer, which corresponds to the human pancreatic carcinoma. After 3 and 5 months of treatment, enalapril was able to significantly delay progression of mPanINs in LSL-KrasG12D; Pdx1-Cre mice (p<0.05). Furthermore, development of invasive pancreatic cancer in LSL-KrasG12D; LSL-Trp53R172H; Pdx1-Cre transgenic mice was partially inhibited by enalapril. Invasive pancreatic cancer was identified in 15 of 25 (60%) LSL-KrasG12D; LSL-Trp53R172H; Pdx1-Cre untreated control mice, but in four of 17 (23.5%, p=0.03) in mice treated with enalapril. Using real-time PCR we found a significant downregulation of the target genes VEGF (p < 0.05) and RelA (p < 0.05) demonstrating our ability to achieve effective pharmacological levels of enalapril during pancreatic cancer formation in vivo. Conclusion Using a transgenic mouse model that imitates human pancreatic cancer, this study provides first evidence that enalapril are effective chemopreventive agents by delaying the progression of PanINs and partially inhibiting the formation of murine pancreatic cancer.