However, no difference in ADCall was found between the ZDTHA and ZD6126 groups (P = 0.08) (Table (Table11 and Figure Figure2A2A-C). Comparison of ADChigh with ADCall: The performance of ADCall was different with that of ADChigh at the following time points. At 4 h, the ADCall in both the ZDTHA and ZD6126 groups showed a significant decrease inhibitor Nutlin-3a compared to the control group; however, this was not observed for ADChigh in the same two groups. On day 2, the ADChigh of ZDTHA was significantly greater than that of ZD6126 (P = 0.03), but the significant difference was not observed for ADCall between the ZDTHA and ZD6126 groups (P = 0.08) (Table (Table11 and Figure Figure2A2A-C). ADClow and perfusion sensitive ADCperf ADClow: The ADClow of ZDTHA was significantly lower than that of ZD6126 before treatment (P < 0.

05), but it was not for the control group (P = 0.12). No significant differences in ADClow were observed among the three groups at 4 h (P > 0.05 for all). On day 2, the ADClow of ZDTHA was much higher compared to the control group (P = 0.02) (Table (Table11 and Figure Figure2D2D-F). ADCperf: Compared to the control group, tumor ADCperf in both the ZD6126 and ZDTHA groups decreased dramatically at 4 h, most likely due to a rapid vascular shutdown induced by ZD6126 (P = 0.016 and 0.047, respectively). This was followed by a rapid rebound on day 2 in both the ZD6126 and ZDTHA groups (no longer significantly different compared to the control group, P = 0.979 and 0.525, respectively) (Figure (Figure2D-F).2D-F). A significant reduction in the tumor ADCperf of ZDTHA was noted at 4 h compared to the ZD6126 group (P = 0.

025). The ADCperf of ZDTHA still showed a lower level compared to the ZD6126 at 2 d, although there was no significant difference (P = 0.44) (Table (Table11 and Figure Figure2D2D-F). Histology Two days after treatment, the percentages of necrosis compared to the total tumor areas on HE stained tumor sections were significantly higher in both the ZDTHA and ZD6126 groups compared to the control group (P = 0.000 for both). No significant difference was found in the necrotic areas of the ZDTHA and ZD6126 groups (P = 0.09) (Figure (Figure11). DISCUSSION We have demonstrated three main findings in the present study. First, tumor growth was significantly delayed by both ZD6126 and ZDTHA treatments compared to the control group, and a significant delay could be observed only two days after application of a single dose of ZD6126.

In addition, ZDTHA significantly delayed tumor growth than ZD6126, indicating a synergistic anticancer effect of ZD6126 and thalidomide. It has been known that tumors can rapidly regrow due to the residual viable rim when ZD6126 was used alone[2]. It has also been reported that thalidomide, which was reintroduced into clinical practice with its antiangiogenic Entinostat properties, had little or no effect on full-grown tumors like those in our patients, when used alone[4].