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Enhancement of Hypoxia-Induced Tumor Cell Death In vitro and Radiation Therapy In vivo by Use of Small Interfering RNA Targeted to Hypoxia-Inducible Factor-1

¹ Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina; and ² No.1 People’s Hospital, Shanghai Jiao Tong University, Shanghai, China

Hypoxia-inducible factor-1 (HIF-1) is an important transcriptional factor that is activated when mammalian cells experience hypoxia, a tumor microenvironmental condition that plays pivotal roles in tumor progression and treatment. In this study, we examined the idea of down-regulating HIF-1 in tumor cells for therapeutic gain. We show that the expression levels of HIF-1 can be significantly attenuated by use of the recently established small interfering RNA technology in combination with adenovirus-mediated gene transfer. Down-regulation of the HIF-1 protein enhanced hypoxia-mediated tumor cell apoptosis in vitro. Subcutaneous tumor growth was also prevented from cells with attenuated HIF-1 expression. In addition, intratumoral injection of adenovirus encoding the HIF-1-targeted small interfering RNA had a small but significant effect on tumor growth when combined with ionizing radiation. Therefore, our results provide proof of HIF-1 as an effective target for anticancer therapy. They also suggest that an adenovirus-based small interfering RNA gene transfer approach may be a potentially effective adjuvant strategy for cancer treatment.

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