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...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2014-06-01
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| Series: | Neoplasia: An International Journal for Oncology Research |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1476558614000645 |
| _version_ | 1811283101503979520 |
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| author | Richard F. Knoop Moritz Sparn Jens Waldmann Lars Plassmeier Detlef K. Bartsch Matthias Lauth Christoph Hudemann Volker Fendrich |
| author_facet | Richard F. Knoop Moritz Sparn Jens Waldmann Lars Plassmeier Detlef K. Bartsch Matthias Lauth Christoph Hudemann Volker Fendrich |
| author_sort | Richard F. Knoop |
| collection | DOAJ |
| 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-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. |
| first_indexed | 2024-04-13T02:05:36Z |
| format | Article |
| id | doaj.art-11c675ee518c463ca5ef00c36a778785 |
| institution | Directory Open Access Journal |
| issn | 1476-5586 |
| language | English |
| last_indexed | 2024-04-13T02:05:36Z |
| publishDate | 2014-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neoplasia: An International Journal for Oncology Research |
| spelling | doaj.art-11c675ee518c463ca5ef00c36a7787852022-12-22T03:07:29ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55862014-06-0116646347010.1016/j.neo.2014.05.010Chronic Pancreatitis and Systemic Inflammatory Response Syndrome Prevent Impact of Chemotherapy with Gemcitabine in a Genetically Engineered Mouse Model of Pancreatic CancerRichard F. Knoop0Moritz Sparn1Jens Waldmann2Lars Plassmeier3Detlef K. Bartsch4Matthias Lauth5Christoph Hudemann6Volker Fendrich7Department of Surgery, Philipp University Marburg, GermanyDepartment of Surgery, Philipp University Marburg, GermanyDepartment of Surgery, Philipp University Marburg, GermanyDepartment of Surgery, Philipp University Marburg, GermanyDepartment of Surgery, Philipp University Marburg, GermanyInstitute of Molecular Biology and Tumor Research, Philipp University Marburg, GermanyDepartment of Laboratory Medicine and Molecular Diagnostics, Philipp University Marburg, GermanyDepartment of Surgery, Philipp University Marburg, GermanyBACKGROUND 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-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.http://www.sciencedirect.com/science/article/pii/S1476558614000645 |
| spellingShingle | Richard F. Knoop Moritz Sparn Jens Waldmann Lars Plassmeier Detlef K. Bartsch Matthias Lauth Christoph Hudemann Volker Fendrich Chronic Pancreatitis and Systemic Inflammatory Response Syndrome Prevent Impact of Chemotherapy with Gemcitabine in a Genetically Engineered Mouse Model of Pancreatic Cancer Neoplasia: An International Journal for Oncology Research |
| 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 |
| url | http://www.sciencedirect.com/science/article/pii/S1476558614000645 |
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