Synergistic effects of interferon-alpha in combination with chemoradiation on human pancreatic adenocarcinoma

Abstract

AIM:To determine whether IFN- is the agent that turns a slightly effective treatment (radiochemotherapy) into a potent therapy, we tested IFN- for its synergistic properties. METHODS:Eight pancreatic carcinoma cell lines were treated with the single agents and combinations of these. The role of IFN- regarding a) direct inhibitory effects; b) radio and chemosensitizing effects; c) anti-angiogenic properties and d) enhancement of immunogenicity was investigated. RESULTS:Our results show that IFN- has direct inhibitory properties and some synergistic influence as determined by AnnexinV/PI stain and cell count. IFN- is also able to prevent the increase in proliferation rate and VEGF secretion of CDDP resistant cells. Having taken the results from immunogenicity experiments together, we found cells that can be influenced by IFN- but were less susceptible against T cells. Furthermore, high expression of MHC molecules, CD118, EGF-R and Fas was predictive for a good response. CONCLUSION:In conclusion, IFN- has direct cytotoxic effects, acts as a radiosensitizer and circumvents tumor cell-regrowth after CDDP treatment. These mechanisms may be responsible for the good clinical outcome of CapRI.

Characterization of Primary Renal Carcinoma Cultures

“…All cell lines tested secreted high amounts of IL-6, TGF-␤ , VEGF and IL-8. The levels were much higher than those observed for example in pancreatic carcinoma [26], breast carcinoma [27] or in various hematological malignancies which might be of major importance. IL-6 has been described as an intracrine growth factor for renal carcinoma cell lines [28] .…”

A Randomized Multicentre Phase II Trial Comparing Adjuvant Therapy in Patients with Interferon Alpha-2b and 5-FU Alone or in Combination with Either External Radiation Treatment and Cisplatin (CapRI) or Radiation alone regarding Event-Free Survival – CapRI-2

“…Most of the toxicities are thought to be related to cisplatin. Furthermore, in vivo data indicate that the combination of 5-FU and INF-α2b is responsible for the anti-tumour effect [ 12 , 13 , 16 , 17 ]. Moreover, there are data supporting the idea that radiotherapy is of low effectiveness [ 2 , 20 , 21 ].…”

“…These include: 1) the radio-sensitization effects of INF-α2b and 5-FU [ 9 , 10 ]; 2) enhanced 5-FU based bio-availability; 3) a synergistic inhibition of pyrimidine metabolism with 5-FU and 4) an independent immunomodulatory effect of INF-α2b [ 11 ]. Furthermore, our own data derived from the translational program accompanying the CapRI trial showed especially immunomodulatory and anti-angiogeneic effects of INF-α2b [ 12 - 17 ].…”

Role of radiotherapy in combination with chemotherapy, targeted therapy, and immunotherapy in the management of pancreatic cancer

“…One of the best studied agents is interferon alpha (IFN-α), which is a pleiotropic cytokine with multiple functions including enhancing antiviral and antitumoral responses. IFN-α has been shown to enhance the differentiation and function of DCs and macrophages, promotes CD8 + memory responses, and also enhances the activity of natural killer (NK) cells [30][31][32][33]. Additionally, IFN-α modulates the activity of the proteosome to produce more immunogenic antigens and simultaneously upregulates MHC class I expression, resulting in an increased immunogenic antigen expression on the cell surface [34].…”