The radiosensitizing effect of immunoadjuvant OM-174 requires cooperation between immune and tumor cells through interferon-gamma and inducible nitric oxide synthase
| Autor: | Carlo Chiavaroli, Mark De Ridder, Guy Storme, Valeri N. Verovski, Christinne Monsaert, Dirk Van den Berge, Kalun Law |
|---|---|
| Přispěvatelé: | Medical Imaging and Physical Sciences, Radiation Therapy, Centre for Oncology, Faculty of Medicine and Pharmacy, Emergency Medicine |
| Jazyk: | angličtina |
| Rok vydání: | 2008 |
| Předmět: |
Lipopolysaccharides
Cancer Research Radiosensitizer genetic structures Down-Regulation Nitric Oxide Synthase Type II Nitric Oxide Immunoadjuvant Radiation Tolerance Nitric oxide OM-174 chemistry.chemical_compound Mice Interferon-gamma Immune system Adjuvants Immunologic Interferon Cell Line Tumor medicine Animals Radiology Nuclear Medicine and imaging Interferon gamma RNA Messenger Immunity Cellular Mice Inbred BALB C Radiation biology business.industry Interleukin-18 immunoadjuvant OM-174 inducible nitric oxide synthase Molecular biology Interleukin-12 Cell Hypoxia Up-Regulation Nitric oxide synthase Enzyme Activation Oncology chemistry Immunology biology.protein Antibody business Spleen medicine.drug |
| Zdroj: | Vrije Universiteit Brussel |
| Popis: | PURPOSE: To explore whether antitumor immunoadjuvant OM-174 can stimulate immune cells to produce interferon-gamma (IFN-gamma) and thereby radiosensitize tumor cells. METHODS AND MATERIALS: Splenocytes from BALB/c mice were stimulated by OM-174 at plasma-achievable concentrations (0.03-3 mug/mL), and afterward analyzed for the expression and secretion of IFN-gamma by reverse transcriptase-polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. Stimulated splenocytes were used as a source of IFN-gamma to radiosensitize hypoxic EMT-6 tumor cells through the cytokine-inducible isoform of nitric oxide synthase (iNOS). RESULTS: OM-174 activated the production of IFN-gamma at high levels that reached 70 ng/mL in normoxia (21% oxygen) and 27 ng/mL in tumor-relevant hypoxia (1% oxygen). This caused up to 2.1-fold radiosensitization of EMT-6 tumor cells, which was associated with the iNOS-mediated production of the radiosensitizing molecule nitric oxide, as confirmed by accumulation of its oxidative metabolite nitrite, Western blot analysis, and reverse transcriptase-polymerase chain reaction. Both iNOS activation and radiosensitization were counteracted by neutralizing antibodies against IFN-gamma. The same mechanism of radiosensitization through the IFN-gamma secretion pathway was identified for IL-12 + IL-18, which are known to mediate IFN-gamma responses. Hypoxia displayed a dual effect on the immune-tumor cell interaction, by downregulating the expression of the IFN-gamma gene while upregulating iNOS at transcriptional level. CONCLUSION: Immunoadjuvant OM-174 is an efficient radiosensitizer of tumor cells through activation of the IFN-gamma secretion pathway in immune cells. This finding indicates a rationale for combining immunostimulatory and radiosensitizing strategies and extends the potential therapeutic applications of OM-174. |
| Databáze: | OpenAIRE |
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