The radiosensitizing effect of immunoadjuvant OM-174 requires cooperation between immune and tumor cells through interferon-gamma and inducible nitric oxide synthase
- Academic Hospital Free University Brussels (A.Z.-V.U.B.), Oncology Center, Cancer Research Unit, Brussels (Belgium)
- OM Pharma, Geneva (Switzerland)
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 {mu}g/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.
- OSTI ID:
- 20850273
- Journal Information:
- International Journal of Radiation Oncology, Biology and Physics, Vol. 66, Issue 5; Other Information: DOI: 10.1016/j.ijrobp.2006.07.1381; PII: S0360-3016(06)02784-2; Copyright (c) 2006 Elsevier Science B.V., Amsterdam, Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA); ISSN 0360-3016
- Country of Publication:
- United States
- Language:
- English
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