. 2019 Jun 3;9(1):51.

doi: 10.1186/s13550-019-0521-x.

Elimination of tumor hypoxia by eribulin demonstrated by ¹⁸F-FMISO hypoxia imaging in human tumor xenograft models

Songji Zhao^{1

2}, Wenwen Yu³, Naoyuki Ukon^{4

5}, Chengbo Tan⁴, Ken-Ichi Nishijima^{5

6}, Yoichi Shimizu⁷, Kei Higashikawa^{5

6}, Tohru Shiga⁸, Hiroko Yamashita⁹, Nagara Tamaki⁸, Yuji Kuge^{5

6}

Affiliations

¹ Department of Tracer Kinetics and Bioanalysis, Graduate School of Medicine, Hokkaido University, Sapporo, Japan. zhao-s@fmu.ac.jp.
² Advanced Clinical Research Center, Fukushima Global Medical Science Center, Fukushima Medical University, 1 Hikariga-oka, Fukushima City, Fukushima, 960-1295, Japan. zhao-s@fmu.ac.jp.
³ Department of Tracer Kinetics and Bioanalysis, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
⁴ Advanced Clinical Research Center, Fukushima Global Medical Science Center, Fukushima Medical University, 1 Hikariga-oka, Fukushima City, Fukushima, 960-1295, Japan.
⁵ Central Institute of Isotope Science, Hokkaido University, Sapporo, Japan.
⁶ Department of Integrated Molecular Imaging, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
⁷ Faculty of Pharmaceutical Science, Hokkaido University, Sapporo, Japan.
⁸ Department of Nuclear Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
⁹ Department of Breast Surgery, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.

PMID: 31161539
PMCID: PMC6546772
DOI: 10.1186/s13550-019-0521-x

Elimination of tumor hypoxia by eribulin demonstrated by ¹⁸F-FMISO hypoxia imaging in human tumor xenograft models

Songji Zhao et al. EJNMMI Res. 2019.

. 2019 Jun 3;9(1):51.

doi: 10.1186/s13550-019-0521-x.

Authors

Affiliations

¹ Department of Tracer Kinetics and Bioanalysis, Graduate School of Medicine, Hokkaido University, Sapporo, Japan. zhao-s@fmu.ac.jp.
² Advanced Clinical Research Center, Fukushima Global Medical Science Center, Fukushima Medical University, 1 Hikariga-oka, Fukushima City, Fukushima, 960-1295, Japan. zhao-s@fmu.ac.jp.
³ Department of Tracer Kinetics and Bioanalysis, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
⁴ Advanced Clinical Research Center, Fukushima Global Medical Science Center, Fukushima Medical University, 1 Hikariga-oka, Fukushima City, Fukushima, 960-1295, Japan.
⁵ Central Institute of Isotope Science, Hokkaido University, Sapporo, Japan.
⁶ Department of Integrated Molecular Imaging, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
⁷ Faculty of Pharmaceutical Science, Hokkaido University, Sapporo, Japan.
⁸ Department of Nuclear Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
⁹ Department of Breast Surgery, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.

PMID: 31161539
PMCID: PMC6546772
DOI: 10.1186/s13550-019-0521-x

Abstract

Background: Eribulin, an inhibitor of microtubule dynamics, shows antitumor potency against a variety of solid cancers through its antivascular activity and remodeling of tumor vasculature. ¹⁸F-Fluoromisonidazole (¹⁸F-FMISO) is the most widely used PET probe for imaging tumor hypoxia. In this study, we utilized ¹⁸F-FMISO to clarify the effects of eribulin on the tumor hypoxic condition in comparison with histological findings.

Material and methods: Mice bearing a human cancer cell xenograft were intraperitoneally administered a single dose of eribulin (0.3 or 1.0 mg/kg) or saline. Three days after the treatment, mice were injected with ¹⁸F-FMISO and pimonidazole (hypoxia marker for immunohistochemistry), and intertumoral ¹⁸F-FMISO accumulation levels and histological characteristics were determined. PET/CT was performed pre- and post-treatment with eribulin (0.3 mg/kg, i.p.).

Results: The ¹⁸F-FMISO accumulation levels and percent pimonidazole-positive hypoxic area were significantly lower, whereas the number of microvessels was higher in the tumors treated with eribulin. The PET/CT confirmed that ¹⁸F-FMISO distribution in the tumor was decreased after the eribulin treatment.

Conclusions: Using ¹⁸F-FMISO, we demonstrated the elimination of the tumor hypoxic condition by eribulin treatment, concomitantly with the increase in microvessel density. These findings indicate that PET imaging using ¹⁸F-FMISO may provide the possibility to detect the early treatment response in clinical patients undergoing eribulin treatment.

Keywords: 18F-FMISO PET imaging; Eribulin; Human tumor xenograft model; Remodeling of tumor vasculature; Tumor hypoxia.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

**Fig. 1**
Experimental protocol of this study. The left panel shows the ex vivo study with control (non-treatment) and two eribulin treatment (A, 0.3 and B, 1.0 mg/kg) groups. The right panel shows PET imaging study with control (non-treatment) and eribulin treatment (0.3 mg/kg) groups

**Fig. 2**
Representative images of ¹⁸F-FMISO PET (a) and intratumoral accumulation levels of ¹⁸F-FMISO (b) in ex vivo study groups. The circle shows the tumor region. R, right; L, left

**Fig. 3**
Representative images of ¹⁸F-FMISO ARG (a), pimonidazole IHC (b), H&E staining (c), quantitative analysis of intratumoral ¹⁸F-FMISO accumulation level (d), and %pimonidazole-positive area (e) in the ex vivo study groups

**Fig. 4**
Representative images (a–c) and quantitative analysis (d) of CD31 IHC in the ex vivo groups. Scale bar is 100 μm

**Fig. 5**
¹⁸F-FMISO PET images (a), tumor volumes (b), and quantitative analyses of tumor mean SUV (SUV_mean) (c) in control mice of PET imaging study group

**Fig. 6**
¹⁸F-FMISO PET images (a), tumor volumes (b), and quantitative analyses of tumor mean SUV (SUV_mean) (c) in mice treated with eribulin in PET imaging study group

See this image and copyright information in PMC

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Elimination of tumor hypoxia by eribulin demonstrated by ¹⁸F-FMISO hypoxia imaging in human tumor xenograft models

Affiliations

Elimination of tumor hypoxia by eribulin demonstrated by ¹⁸F-FMISO hypoxia imaging in human tumor xenograft models

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