Sensitization of Hypoxic Tumors to Radiation Therapy Using Oxygen Micro-bubbles and Papaverine
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Radiation therapy is a frequently used treatment method for malignant tumors despite the heterogeneous response in tumors with a hypoxic microenvironment. Specific features in this microenvironment like poorly formed and inefficient vasculature contribute to chronic and cycling hypoxia. Notably, hypoxic tumor cells are three times more radioresistant than normoxic cells, which make hypoxia a key contributor to poor treatment outcome. There have been many previous attempts to re-oxygenate tumors either through increasing the supply or decreasing the demand of oxygen. However, no study has yet been performed to investigate the combined effect of increasing the oxygen supply and decrease the oxygen demand in vivo.
There are two main purposes of this study, which are tested in two individual rounds: 1) assessing the combined effect of oxygen micro-bubbles and papaverine in alleviating tumor hypoxia in murine sarcoma model and 2) assessing the combined effect of oxygen micro bubble and papaverine as radiosensitizers. Using nu-nu mice with subcutaneous sarcoma tumors, the change resulting from oxygen micro-bubbles and/or papaverine was evaluated by changes in hemoglobin saturation from baseline and control groups. By further monitoring tumor growth and percent hemoglobin saturation after administration of papaverine and oxygen micro-bubbles followed by a single fraction of 15 Gy of radiation, we also tested the effects of the combination of papaverine and oxygen micro-bubbles in tumor control and oxygenation.
The result of the non-irradiated study showed no significant improvement of the combination of oxygen micro-bubbles and papaverine group in the percent hemoglobin saturation level compared with other groups. Notably, percent hemoglobin saturation changes are rather heterogenous within each group. However, this unexpected result may be due to certain practical and theoretic limitations. The follow-up immunohistochemistry study may provide more information of the overall oxygenation of the tumors. For the irradiated study, the percent hemoglobin saturation measurement of the oxygen micro-bubbles and papaverine group is the only one showed improved level the day after the treatment compared with the day before treatment. The combination of oxygen micro-bubbles and papaverine did not show increased tumor control after radiotherapy compared with other groups. However, it should be noted that there are some practical and theoretical limitations in the study that may have contributed in this which is discussed in detail in the discussion chapter. Further studies might be needed to investigate the reasons for this unexpected result.
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