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

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.

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