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

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

doi:10.3389/fonc.2021.672047

Abstract

ObjectiveThis 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 methodsEstablishing 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.ResultsAt 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).ConclusionAnti-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.

Highlights

Due to the heterogeneity between or within tumors, the efficacy of conventional cytotoxic agents remains limited
The standard apparent diffusion coefficient (ADC) values was positive correlated with transferase-mediated dUTP nick end labeling (TUNEL) (r=0.672, P=0.017) and negative correlated with Ki-67 (r=0.873, P
The hypoxic microenvironment caused by VEGF(R) inhibitors can stimulate metastasis [12], which may result in treatment failure

Summary

Introduction

Due to the heterogeneity between or within tumors, the efficacy of conventional cytotoxic agents remains limited. Targeting the tumor vasculature is another strategy for cancer therapy, especially vascular targeting therapy. The vascular supply of oxygen and nutrients is indispensable for tumor growth. Vascular targeting therapy has been proven to suppress tumor growth [1, 2]. Bevacizumab is an antiangiogenic agent that can bind to VEGF-A and reduce the tumor neovascularization. The expression of angiogenic factors (e.g., VEGF) would be upregulated in tumor cells in order to promote angiogenesis, which may result in treatment failure. TH-302 (evofosfamide) is the second-generation HAP that can be activated under hypoxic conditions by the reduction of its 2nitroimidazole moiety and release the toxic effector bromoisophosphoramide mustard (Br-IPM), which can crosslink DNA, leading to tumor cell death [3]

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Conclusion