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.
Highlights
Worldwide, gastric cancer is the fourth most common malignancy and the second most fatal (Alberts et al 2003; Edwards et al 2006)
We found that phosphorylation of checkpoint protein kinase 1 (Chk1) was 2- to 3-fold higher in the two dose groups, compared to controls, and maintained for up 1 h
We have identified the gastric cancer-derived AGS
Summary
Gastric cancer is the fourth most common malignancy and the second most fatal (Alberts et al 2003; Edwards et al 2006). The available clinical data in the treatment of gastric carcinoma have demonstrated that radiation therapy has a role for improving local control and, in combination chemotherapy, survival (Alberts et al 2003; Edwards et al 2006; Das and Ajani, 2005). About half of patients are resistant to chemotherapy Another limitation is cumulative, systemic toxicity after typical prolonged and high-dose drug therapy that often compromises “full-dose” therapy (Alberts et al 2003; Das and Ajani, 2005; Oehler and Ciernik, 2006). A great deal of interest has focused on the search of new strategies to enhance the anticancer effects of lower drug and/or radiation doses
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