Monitoring Treatment Efficacy of Antiangiogenic Therapy Combined With Hypoxia-Activated Prodrugs Online Using Functional MRI

Mengjie Ma; Jianye Liang; Dong Zhang; Xi Xu; Qingqing Cheng; Zeyu Xiao; Changzheng Shi; Liangping Luo

doi:10.3389/fonc.2021.672047

Monitoring Treatment Efficacy of Antiangiogenic Therapy Combined With Hypoxia-Activated Prodrugs Online Using Functional MRI

Front Oncol. 2021 Apr 30:11:672047. doi: 10.3389/fonc.2021.672047. eCollection 2021.

Authors

Mengjie Ma¹, Jianye Liang², Dong Zhang¹, Xi Xu¹, Qingqing Cheng¹, Zeyu Xiao¹, Changzheng Shi¹, Liangping Luo¹

Affiliations

¹ Medical Imaging Center, The First Affiliated Hospital of Jinan University, Guangzhou, China.
² Department of Medical Imaging, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.

Abstract

Objective: This study aimed to investigate the effectiveness of intravoxel incoherent motion (IVIM) diffusion-weighted imaging (DWI) and blood oxygen level-dependent (BOLD) magnetic resonance imaging (MRI) in monitoring tumor responses to antiangiogenic therapy combined with hypoxia-activated prodrugs (HAPs).

Materials and methods: Establishing colon cancer xenograft model by subcutaneously injecting the HCT116 cell line into BALB/C nude mice. Twenty-four tumor-bearing mice were randomly divided into four groups and injected with bevacizumab combined with TH-302 (A), bevacizumab (B), TH-302 (C), or saline (D) on days 1, 4, 7, 10 and 13. Functional MRI was performed before and at 3, 6, 9, 12 and 15 days after treatment. Pathologic examinations, including HE staining, HIF-1α and CD31 immunohistochemical staining, and TUNEL and Ki-67 immunofluorescent staining, were performed after the last scan.

Results: At the end of the study, Group A showed the lowest tumor volume, followed by Groups B, C, and D (F=120.652, P<0.001). For pathologic examinations, Group A showed the lowest percentage of CD31 staining (F=73.211, P<0.001) and Ki-67 staining (F=231.170, P<0.001), as well as the highest percentage of TUNEL staining (F=74.012, P<0.001). Moreover, the D* and f values exhibited positive correlations with CD31 (r=0.868, P<0.001, and r=0.698, P=0.012, respectively). R2* values was positively correlated with HIF-1α (r=0.776, P=0.003). D values were positively correlated with TUNEL (r=0.737, P=0.006) and negatively correlated with Ki-67 (r=0.912, P<0.001). The standard ADC values were positive correlated with TUNEL (r=0.672, P=0.017) and negative correlated with Ki-67 (r=0.873, P<0.001).

Conclusion: Anti-angiogenic agents combined with HAP can inhibit tumor growth effectively. In addition, IVIM-DWI and BOLD-MRI can be used to monitor the tumor microenvironment, including perfusion, hypoxia, cell apoptosis and proliferation, in a noninvasive manner.

Keywords: BOLD-MRI; IVIM-DWI; antiangiogenic therapy; hypoxia; hypoxia-activated prodrugs.