Cargando…

Chronic Pancreatitis and Systemic Inflammatory Response Syndrome Prevent Impact of Chemotherapy with Gemcitabine in a Genetically Engineered Mouse Model of Pancreatic Cancer()()

BACKGROUND AND AIMS: 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...

Descripción completa

Detalles Bibliográficos
Autores principales: Knoop, Richard F., Sparn, Moritz, Waldmann, Jens, Plassmeier, Lars, Bartsch, Detlef K., Lauth, Matthias, Hudemann, Christoph, Fendrich, Volker
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Neoplasia Press 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4198747/
https://www.ncbi.nlm.nih.gov/pubmed/24953430
http://dx.doi.org/10.1016/j.neo.2014.05.010
_version_ 1782339778177400832
author Knoop, Richard F.
Sparn, Moritz
Waldmann, Jens
Plassmeier, Lars
Bartsch, Detlef K.
Lauth, Matthias
Hudemann, Christoph
Fendrich, Volker
author_facet Knoop, Richard F.
Sparn, Moritz
Waldmann, Jens
Plassmeier, Lars
Bartsch, Detlef K.
Lauth, Matthias
Hudemann, Christoph
Fendrich, Volker
author_sort Knoop, Richard F.
collection PubMed
description BACKGROUND AND AIMS: 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. 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.
format Online
Article
Text
id pubmed-4198747
institution National Center for Biotechnology Information
language English
publishDate 2014
publisher Neoplasia Press
record_format MEDLINE/PubMed
spelling pubmed-41987472014-10-21 Chronic Pancreatitis and Systemic Inflammatory Response Syndrome Prevent Impact of Chemotherapy with Gemcitabine in a Genetically Engineered Mouse Model of Pancreatic Cancer()() Knoop, Richard F. Sparn, Moritz Waldmann, Jens Plassmeier, Lars Bartsch, Detlef K. Lauth, Matthias Hudemann, Christoph Fendrich, Volker Neoplasia Article BACKGROUND AND AIMS: 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. 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. Neoplasia Press 2014-06-20 /pmc/articles/PMC4198747/ /pubmed/24953430 http://dx.doi.org/10.1016/j.neo.2014.05.010 Text en © 2014 Neoplasia Press, Inc. http://creativecommons.org/licenses/by-nc-nd/3.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).
spellingShingle Article
Knoop, Richard F.
Sparn, Moritz
Waldmann, Jens
Plassmeier, Lars
Bartsch, Detlef K.
Lauth, Matthias
Hudemann, Christoph
Fendrich, Volker
Chronic Pancreatitis and Systemic Inflammatory Response Syndrome Prevent Impact of Chemotherapy with Gemcitabine in a Genetically Engineered Mouse Model of Pancreatic Cancer()()
title Chronic Pancreatitis and Systemic Inflammatory Response Syndrome Prevent Impact of Chemotherapy with Gemcitabine in a Genetically Engineered Mouse Model of Pancreatic Cancer()()
title_full Chronic Pancreatitis and Systemic Inflammatory Response Syndrome Prevent Impact of Chemotherapy with Gemcitabine in a Genetically Engineered Mouse Model of Pancreatic Cancer()()
title_fullStr Chronic Pancreatitis and Systemic Inflammatory Response Syndrome Prevent Impact of Chemotherapy with Gemcitabine in a Genetically Engineered Mouse Model of Pancreatic Cancer()()
title_full_unstemmed Chronic Pancreatitis and Systemic Inflammatory Response Syndrome Prevent Impact of Chemotherapy with Gemcitabine in a Genetically Engineered Mouse Model of Pancreatic Cancer()()
title_short Chronic Pancreatitis and Systemic Inflammatory Response Syndrome Prevent Impact of Chemotherapy with Gemcitabine in a Genetically Engineered Mouse Model of Pancreatic Cancer()()
title_sort chronic pancreatitis and systemic inflammatory response syndrome prevent impact of chemotherapy with gemcitabine in a genetically engineered mouse model of pancreatic cancer()()
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4198747/
https://www.ncbi.nlm.nih.gov/pubmed/24953430
http://dx.doi.org/10.1016/j.neo.2014.05.010
work_keys_str_mv AT knooprichardf chronicpancreatitisandsystemicinflammatoryresponsesyndromepreventimpactofchemotherapywithgemcitabineinageneticallyengineeredmousemodelofpancreaticcancer
AT sparnmoritz chronicpancreatitisandsystemicinflammatoryresponsesyndromepreventimpactofchemotherapywithgemcitabineinageneticallyengineeredmousemodelofpancreaticcancer
AT waldmannjens chronicpancreatitisandsystemicinflammatoryresponsesyndromepreventimpactofchemotherapywithgemcitabineinageneticallyengineeredmousemodelofpancreaticcancer
AT plassmeierlars chronicpancreatitisandsystemicinflammatoryresponsesyndromepreventimpactofchemotherapywithgemcitabineinageneticallyengineeredmousemodelofpancreaticcancer
AT bartschdetlefk chronicpancreatitisandsystemicinflammatoryresponsesyndromepreventimpactofchemotherapywithgemcitabineinageneticallyengineeredmousemodelofpancreaticcancer
AT lauthmatthias chronicpancreatitisandsystemicinflammatoryresponsesyndromepreventimpactofchemotherapywithgemcitabineinageneticallyengineeredmousemodelofpancreaticcancer
AT hudemannchristoph chronicpancreatitisandsystemicinflammatoryresponsesyndromepreventimpactofchemotherapywithgemcitabineinageneticallyengineeredmousemodelofpancreaticcancer
AT fendrichvolker chronicpancreatitisandsystemicinflammatoryresponsesyndromepreventimpactofchemotherapywithgemcitabineinageneticallyengineeredmousemodelofpancreaticcancer