The presence of hypoxic regions within solid
tumors is caused by an imbalance between cell proliferation and angiogenesis. Such regions may facilitate the onset of recurrence after
radiation therapy and
chemotherapy, as hypoxic cells show resistance to these treatments. We found that
tempol, a
nitroxide, strongly induces the accumulation of
hypoxia-inducible factor (HIF)-1α, particularly under conditions of
hypoxia. We, therefore, evaluated whether
tempol enhances the gene expression via HIF-1α, potentially leading to various applications for cancer gene
therapy targeting hypoxic cells. Consequently, following treatment with
tempol under
hypoxia, the
luciferase (Luc) activity in the cells transfected with the plasmid containing the luc gene with the
oxygen-dependent degradation domain and a promoter composed of
hypoxia-responsive elements increased up to approximately 10-fold compared to that observed in cells treated identically with the exception of
tempol. The plasmid constructed by replacing the luc gene with the fcy::fur fusion gene as a suicide gene, strongly induced the accumulation of the Fcy::Fur fusion
protein, only when incubated in the presence of the hypoxic mimic CoCl2 and
tempol. The transfected cells were successfully killed with the addition of
5-fluorocytosine to the cell culture according to the fcy::fur fusion gene expression. As similar but lesser enhancement of the Luc activity was also observed in solid
tumor tissues in nude mice, this strategy may be applied for hypoxic
cancer eradication.