MRI Study Of Antiangiogenic Agents Combined With Hypoxia Activated Prodrugs In The Treatment Of Nude Mice Xenograft Model Of Colon Cancer

Objective: Based on magnetic resonance(intravoxel-incoherent-motion diffusion-weighed imaging,IVIM-DWI)and(blood oxygenation level-dependent magnetic resonance imaging,BOLD-MRI)sequences to monitor the vivo efficacy of antiangiogenic agents combined with hypoxia activated prodrugs in the treatment of nude mice xenograft model of colon cancer.To explore the application value of IVIM-DWI and BOLD-MRI in evaluating micro-perfusion and hypoxia microenvironment of solid tumors comparison to immunohistochemical analysis.Methods: The subcutaneous xenograft model of colon cancer was established in nude mice with HCT116 cell line 18 nude mice were randomly divided into 3 groups,defined as Group A(bevacizumab+TH-302),Group B(bevacizumab)and Group C(saline).IVIM-DWI and BOLD examinations were performed on baseline and 1d,4d,7h,10 d,14d after treatment,and the variation trend of relevant parameters(D,D*,f and R2* values)were observed.At the end of the experiment,three nude mice in each group were randomly selected for pathological examinations.which mainly included hematoxylin-eosin staining,HIF-1? and CD31 immunohistochemical staining,and TUNEL,KI-67 fluorescent staining.Data were analyzed by one-way analysis of variance and Pearson correlation was used to analyze the correlation between magnetic resonance imaging parameters and pathological indicators.Results: Morphological results showed that the tumor volumes at the end of treatment of Group A were slightly larger than that at the baseline(F=7.499,P<0.001).On day 7/10/14,the tumor volumes of Group A were significantly smaller than that of Group B and Group C at the same time point(P<0.001).The magnetic resonance results showed that the D values at the end of treatment of Group A were higher than that at the baseline(F=13.816,P<0.001).On day 4/7/10/14,the D values of Group A were significantly higher than that of Group B and Group C at the same time point(P=0.001-0.002).The D* values at the end of treatment of Group A were lower than that at the baseline(F=26.673,P<0.001).On day 4/7/10/14,the D* values of Group A were significantly lower than that of Group C at the same time point(P=0.001-0.031).The f values at the end of treatment of Group A were lower than that at the baseline(F=19.032,P<0.001).On day 4/7/10/14,the f values of Group A were significantly lower than that of Group C at the same time point(P=0.001-0.029).The R2* values at the end of treatment of Group A were higher than that at the baseline(F=45.054,P<0.001).On day 4/7/10/14,the R2* values of Group A were significantly higher than that of Group C at the same time point(P<0.001).Pathological results showed that TUNEL staining of Group A were higher than other groups,followed by Group B,Group C(F=13.722,P=0.006).Ki-67 staining were the lowest in Group A,followed by Group C,Group B(F=12.063,P=0.008).CD31 staining,Group B were lower than other groups,followed by Group A,Group C(F=17.428,P=0.003).HIF-1? staining were the highest in Group A,followed by Group B,Group C(F=7.855,P=0.021).Correlation analyze results showed that,D* value(r=0.716,P=0.030)as well as f value(r=0.772,P=0.015)had a good correlation with CD31 staining,R2* value had a good correlation with HIF-1? staining(r=0.682,P=0.043),and D value had a good correlation with TUNEL(r=0.686,P=0.040)and KI-67(r=0.787,P=0.012).Conclusion: IVIM-DWI and BOLD-MRI can effectively evaluate the characteristics of micro-perfusion,hypoxia microenvironment and tumor proliferation activity in solid tumors.The combination of angiogenesis inhibitors and hypoxia activated prodrugs can play a synergistic antitumor effect in the treatment of nude mice xenograft model of colon cancer.