title: Chronic pancreatitis and systemic inflammatory response syndrome prevent impact of chemotherapy with gemcitabine in a genetically engineered mouse model of pancreatic cancer.
abstract: OBJECTIVE
  BACKGROUND AND AIMSGemcitabine 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-Kras(G12D/+);LSL-Trp53(R172H/+) 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.
  
  
  CONCLUSIONS
  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.
authors: Department of Surgery, Philipp University Marburg, Germany.
authors: Richard F
authors: RF
authors: Knoop
authors: Department of Surgery, Philipp University Marburg, Germany.
authors: Moritz
authors: M
authors: Sparn
authors: Department of Surgery, Philipp University Marburg, Germany.
authors: Jens
authors: J
authors: Waldmann
authors: Department of Surgery, Philipp University Marburg, Germany.
authors: Lars
authors: L
authors: Plassmeier
authors: Department of Surgery, Philipp University Marburg, Germany.
authors: Detlef K
authors: DK
authors: Bartsch
authors: Institute of Molecular Biology and Tumor Research, Philipp University Marburg, Germany.
authors: Matthias
authors: M
authors: Lauth
authors: Department of Laboratory Medicine and Molecular Diagnostics, Philipp University Marburg, Germany.
authors: Christoph
authors: C
authors: Hudemann
authors: Department of Surgery, Philipp University Marburg, Germany. Electronic address: fendrich@med.uni-marburg.de.
authors: Volker
authors: V
authors: Fendrich
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000494:pharmacology*; D021441:Carcinoma, Pancreatic Ductal / Q000150:complications / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D004195:Disease Models, Animal; D016158:Genes, p53; D011905:Genes, ras; D018398:Homeodomain Proteins / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000150:complications* / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D050500:Pancreatitis, Chronic / Q000150:complications* / Q000378:metabolism; D010766:Phosphorylation; D050796:STAT3 Transcription Factor / Q000378:metabolism; D018746:Systemic Inflammatory Response Syndrome / Q000150:complications* / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics; D016896:Treatment Outcome; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D016207:Cytokines; D018398:Homeodomain Proteins; D016328:NF-kappa B; D050796:STAT3 Transcription Factor; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D003841:Deoxycytidine; D000093542:Gemcitabine