TY  - GEN
TI  - The Immunomodulatory Impact of Interferon-alpha in Combination with Chemoradiation of Pancreatic Adenocarcinoma (CapRI)
AV  - public
KW  - pancreatic adenocarcinoma 
KW  -  combination therapy 
KW  -  interferon-alpha 2b 
KW  -  NK cells
Y1  - 2005///
A1  - Patrut, Emilia-Maria
UR  - http://www.ub.uni-heidelberg.de/archiv/5884
N2  - Data from a phase II trial combining chemoradiotherapy with IFN-alpha (CapRI scheme) for adjuvant treatment of pancreatic carcinoma are very encouraging. Hypothesizing that IFN-alpha is the agent which significantly improves radiochemotherapy this work focuses on the immunomodulatory effect of IFN-alpha in this regimen. Eight human ductal pancreatic carcinoma cell lines were treated with the CapRI scheme (5-Fluorouracil, cisplatin, IFN-alpha and radiation). Peripheral blood lymphocytes, NK and T cells were preincubated with 1,000 U/ml IFN-alpha over 24 hours and tested in cytotoxicity assays against these cell lines and the mechanism of apoptosis induction was investigated, as well as the direct effect of IFN-alpha on pancreatic carcinoma cells regarding their immunogenicity and the influence on the DNA binding activity of the nuclear transcription factor NF-kappaB. The results showed an increase in cytotoxic activity of peripheral blood lymphocytes after IFN-alpha treatment from 12.5% to 34.3% (p<0.05). This increase in cytotoxicity was due to the NK cells as shown after depletion of T cells (T cells 4% lysis, NK cells 42.7% lysis) and was mediated by Fas-induced apoptosis, as well as by perforin release. Pretreatment of tumor cells with 5-FU and its combinations showed a significant increase in the susceptibility of tumor cells to NK cells (untreated tumor cells 34.3%, CapRI scheme 69.1%). While there was no significant difference between the whole CapRI scheme and chemoradiotherapy regarding cell proliferation rate and apoptosis induction, the cytotoxic effect of IFN-alpha stimulated lymphocytes against CapRI-treated pancreatic carcinoma cells was significantly higher than the effect of unstimulated lymphocytes against chemoradiotreated tumor cells (CapRI scheme -120.3%, chemoradiotherapy -75.2%, p=0.0001). IFN-alpha alone was able to increase the immunogenicity of pancreatic carcinoma cell lines increasing the mean expression of MHC class I in a significant manner which makes the tumor cells more susceptible to T cell cytotoxicity. In selected pancreatic carcinoma cell lines IFN-alpha might inhibit the DNA-binding activity of nuclear transcription factor NF-kappaB. IFN-alpha activates NK cells against pancreatic carcinoma cells and 5 FU treatment makes tumor cells more susceptible. These mechanisms may be responsible for the improved clinical outcome of CapRI. 
ID  - heidok9377
ER  -