|University of Virginia
|glioma; hypoxia; radiotherapy; oxygen
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Glioblastoma multiforme (GBM) is the most common and lethal form of brain cancer, with an average patient life expectancy of just 12-15 months beyond diagnosis. These tumors are also highly resistant to chemo- and radiotherapy. Tumor cell resistance to radiotherapy is generally thought to occur due to the low levels of molecular oxygen present in hypoxic tumor regions, which results in reduced DNA damage and enhanced cellular defense mechanisms. Experimental and clinical efforts to counteract tumor hypoxia during radiotherapy are often limited by an attendant increase in the sensitivity of healthy brain tissue to radiation. However, the presence of heightened levels of molecular oxygen during radiotherapy, while conventionally deemed critical for adjuvant oxygen therapy to sensitize hypoxic tumor tissue, might not actually be necessary. The guiding hypothesis of this thesis is that oxygen pretreatment of hypoxic glioma cells produces a shift in the cellular and molecular underpinnings of hypoxic tumor cell treatment resistance, creating a sustained period of radiation vulnerability in tumor cells, even after these cells have returned to hypoxic conditions. We evaluated this concept using a U87-luciferase xenograft glioma model and in vitro models of tumor hypoxia, and were able to test the efficacy of oxygen pretreatment in producing radiosensitization in hypoxic tumor tissue. The results presented herein demonstrate that oxygen-induced radiosensitization of tumor tissue occurs in GBM xenografts, as seen by suppression of tumor growth and increased animal survival. Additionally, rodent and human glioma cells, and human glioma stem cells, exhibit prolonged enhanced vulnerability to radiation after oxygen pretreatment in vitro, even when radiation is delivered under hypoxic conditions. The presence of nuclear HIF-1α protein corresponds closely with cellular resistance to radiotherapy in vitro and, interestingly, over-expression of HIF-1α in glioma cells reduces the radiosensitization effects induced by oxygen pretreatment. These results indicate that this sustained oxygen-induced radiosensitization is mediated, in part, via changes in HIF-1-dependent mechanisms. Importantly, this work shows that an identical duration of transient hyperoxic exposure does not sensitize normal human astrocytes to radiation in vitro. Taken together, my findings indicate that briefly pre-treating tumors with elevated levels of oxygen prior to radiotherapy may represent a means for selectively targeting radiation-resistant hypoxic cancer cells, and could serve as a safe and effective adjuvant to radiation therapy for patients with GBM.