Abstract
1-(3-C-Ethynyl-β-D-ribo-pentofuranosyl)cytosine (TAS106, ECyd) has previously shown to enhance the antitumor efficacy of X irradiation. However, the effect of TAS106 on hypoxic cells in tumors, which are associated with poor prognosis for radiotherapy, remains unknown. In this study, hypoxia (oxygen concentration < 20 mmHg) was achieved by passing 95% N2 and 5% CO2 gases continuously in a gas-exchangeable chamber. We showed that a low dose of TAS106 induced radiosensitization of apoptosis to human gastric adenocarcinoma MKN45 and MKN28 cells under hypoxia similarly to normoxia in vitro. The reduction of HIF-1α gene expression using the specific antisense oligodeoxynucleotides also enhances X-ray-induced cell death in hypoxic tumor cells dramatically. The accumulation of HIF-1α which was observed under hypoxia, was decreased to the level of normoxia in the presence of 0.1 μM TAS106. In vivo study, MKN45 cells were inoculated into the footpad in severe combined immunodeficient (SCID) mice. Histological analyses revealed a significant reduction of tumor hypoxic regions and apoptotic induction of hypoxic cells in mice treated with a low dose of X-rays (2 Gy) and TAS106 (0.5mg/kg), via probably the inhibition of HIF-1α expression by TAS106. These results suggested that TAS106 acted a strong radiosensitizer through the inhibition of HIF-1α pathway and a potent agent against radiotherapy-resistant hypoxic cells in solid tumors.
