1. ¹Laboratory of Radiation Biology, Department of Environmental Veterinary Sciences, Graduate School of Veterinary Medicine, Hokkaido University, N18 W9, Sapporo 060-0818, Japan
2. ²Laboratory of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Hokkaido University, N12 W6, Sapporo 060-0812, Japan
3. ³Department of Radiological Technology, Hirosaki University School of Health Sciences, 66-1 Hon-cho, Hirosaki, 036-8564, Japan

Correspondence: Dr O Inanami, E-mail: inanami@vetmed.hokudai.ac.jp

Received 27 June 2008; Revised 15 September 2008; Accepted 17 September 2008; Published online 14 October 2008.

Abstract

In a previous study, we showed that a novel anticancer drug, 1-(3-C-ethynyl--D-ribo-pentofuranosyl)cytosine (TAS106, ECyd) increased the antitumour efficacy of X-irradiation. However, its effects on hypoxic cells in tumours remain unclarified. Here, we show that TAS106 enhances the induction of apoptosis in X-irradiated human gastric adenocarcinoma MKN45 and MKN28 cells under hypoxia in vitro. At the same time, the accumulation of HIF-1 observed under hypoxia was shown to be decreased to the level of normoxia in the presence of 0.1 M TAS106. To study the function of HIF-1 protein in apoptosis of hypoxic cells, we employed an HIF-1 reductive approach using its specific antisense oligodeoxynucleotide. The reduction of HIF-1 gene expression dramatically enhanced X-ray-induced apoptosis in hypoxic cells. In in vivo experiments in which MKN45 cells were transplanted into severe combined immunodeficient (SCID) mice, TAS106 (0.5 mg kg^-1) suppressed HIF-1 expression and subsequently reduced the area of the hypoxic region in the tumour and enhanced the induction of apoptosis in the hypoxic region when combined with 2 Gy of X-irradiation. These results suggest the possibility that TAS106 acts as a potent radiosensitiser through the inhibition of HIF-1 expression and can be a useful agent against radiotherapy-resistant hypoxic cells in solid tumours.