Evaluation of metronomic chemotherapy response using diffusion and dynamic contrast-enhanced MRI.

Mehran Baboli,Jin Zhang,Melanie Freed,Sungheon Gene Kim,Kerryanne V Winters

doi:10.1371/journal.pone.0241916

Mehran Baboli, Jin Zhang + Show 3 more

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https://doi.org/10.1371/journal.pone.0241916

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Abstract

To investigate the feasibility of using diffusion MRI (dMRI) and dynamic contrast-enhanced (DCE) MRI to evaluate the treatment response of metronomic chemotherapy (MCT) in the 4T1 mammary tumor model of locally advanced breast cancer. Twelve Balb/c mice with metastatic breast cancer were divided into treated and untreated (control) groups. The treated group (n = 6) received five treatments of anti-metabolite agent 5-Fluorouracil (5FU) in the span of two weeks. dMRI and DCE-MRI were acquired for both treated and control groups before and after MCT. Immunohistochemically staining and measurements were performed after the post-MRI measurements for comparison. The control mice had significantly (p<0.005) larger tumors than the MCT treated mice. The DCE-MRI analysis showed a decrease in contrast enhancement for the control group, whereas the MCT mice had a more stable enhancement between the pre-chemo and post-chemo time points. This confirms the antiangiogenic effects of 5FU treatment. Comparing amplitude of enhancement revealed a significantly (p<0.05) higher enhancement in the MCT tumors than in the controls. Moreover, the MCT uptake rate was significantly (p<0.001) slower than the controls. dMRI analysis showed the MCT ADC values were significantly larger than the control group at the post-scan time point. dMRI and DCE-MRI can be used as potential biomarkers for assessing the treatment response of MCT. The MRI and pathology observations suggested that in addition to the cytotoxic effect of cell kills, the MCT with a cytotoxic drug, 5FU, induced changes in the tumor vasculature similar to the anti-angiogenic effect.

Highlights

Metronomic chemotherapy (MCT) is to administer conventional cytotoxic drugs in low doses frequently or continuously over extended periods without prolonged breaks [1, 2]
The dynamic contrast-enhanced (DCE)-MRI analysis showed a decrease in contrast enhancement for the control group, whereas the MCT mice had a more stable enhancement between the pre-chemo and postchemo time points
This confirms the antiangiogenic effects of 5FU treatment

Summary

Introduction

Metronomic chemotherapy (MCT) is to administer conventional cytotoxic drugs in low doses frequently or continuously over extended periods without prolonged breaks [1, 2]. Previous studies have shown that MCT induces anti-angiogenic effects [3, 4] and hinders recovery of the tumor vasculature by suppressing mobilization of marrow-derived circulating endothelial progenitors (CEPs) [5]. We hypothesize that quantitative MRI methods could elucidate the tumor microenvironment changes induced by MCT, as MRI has been used extensively to study cancer treatment response [12,13,14,15,16,17,18,19,20]

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