The Effect of Docetaxel (Taxotere®) on Human Gastric Cancer Cells Exhibiting Low-Dose Radiation Hypersensitivity

Abstract

Low-dose radiation hypersensitivity (HRS) describes a phenomenon of excessive sensitivity to X ray doses <0.5 Gy. Docetaxel is a taxane shown to arrest cells in the G 2 /M phase of the cell cycle. Some previous studies suggested that HRS might result from the abrogation of the early G 2 checkpoint arrest. First we tested whether HRS occurs in gastric cancer—derived cells, and whether pre-treatment of cells with low docetaxel concentrations can enhance the magnitude of HRS in gastric cancer cells. The results demonstrated HRS at ~0.3 Gy and the synergy between 0.3 Gy and docetaxel (3 nM for 24 h), and the additivity of other drug/dose combinations. The synergistic effect was associated with a significant docetaxel-induced G 2 accumulation. Next, we evaluated in time-course experiments ATM kinase activity and proteins associated with the induction and maintenance of the early G 2 checkpoint. The results of multi-immunoblot analysis demonstrate that HRS does not correlate with the ATM-dependent early G 2 checkpoint arrest. We speculate that G 2 checkpoint adaptation, a phenomenon associated with a prolonged cell cycle arrest, might be involved in HRS. Our results also suggest a new approach for the improvement the effectiveness of docetaxel-based radiotherapy using low doses per fraction.