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 G2/M phase of the cell cycle. Some previous studies suggested that HRS might result from the abrogation of the early G2 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 G2 accumulation. Next, we evaluated in time-course experiments ATM kinase activity and proteins associated with the induction and maintenance of the early G2 checkpoint. The results of multi-immunoblot analysis demonstrate that HRS does not correlate with the ATM-dependent early G2 checkpoint arrest. We speculate that G2 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.

Concentration-dependent radiosensitizing effect of docetaxel in esophageal squamous cell carcinoma cells

“…Among them, DTX is useful for many types of cancer including nasopharyngeal (8), gastric (9,10), breast (11), prostate (12), lung (13), thyroid (14) and esophageal cancer (15). It has been widely recognized that DTX enhances radiosensitivity in various cancers in vitro and in vivo (16)(17)(18). To date, DTX has been shown to be clinically useful as an active agent in CRT treatment regimens involving laryngeal/hypopharyngeal cancers (19).…”

Synergistic enhancement of cell death by triple combination therapy of docetaxel, ultrasound and microbubbles, and radiotherapy on PC3 a prostate cancer cell line

“…This suggests that synergism in TXT + XRT therapy partly depends on chemotherapy and radiotherapy doses. The enhanced efficacy of double combination therapy of TXT and XRT may be associated with the TXT causing a cell cycle arrest in the radiosensitive G2/M phase of the cell cycle and enhanced apoptosis related to ceramide production [ 36 , 37 ].…”

A Logarithmic Formula to Describe the Relationship between the Increased Radiosensitivity at Low Doses and the Survival at 2 Gray

“…7,[17][18][19][20][21][22][23][24][25] Data points and their error bars were obtained using programming techniques described in previous work. 26 Each survival data set for a given cell line were fitted to the IR model and the RCR model using all data points on the curve.…”