Abstract
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Objectives Pathological angiogenesis generates an abnormal microenvironment in tumors, characterized by elevated interstitial fluid pressure and hypoxia. Hypoxia is an important resistance factor in radio- and chemotherapies. Eribulin is an inhibitor of microtubule dynamics and have an antivascular (antiangiogenesis or vascular-disrupting) activity that can target abnormal tumor vessels. Thus, eribulin can induce remodeling of tumor vasculature through a novel antivascular activity and improve tumor hypoxic condition. The remodeling of tumor vasculature may enhance the delivery of chemotherapeutic drugs or increase the sensitivity to radiotherapy. 18F-fluoromisonidazole (18F-FMISO) is the most widely used probe for imaging tumor hypoxia. Measurement of tumor hypoxic condition by 18F-FMISO PET may be used to assess early responses to a therapy. Thus, we clarified whether 18F-FMISO hypoxia imaging can evaluate early the effects of eribulin on remodeling of tumor vasculature in a human breast cancer cell xenograft.
Methods A human breast cancer cell xenograft (MDA-MB435s) was established in nude mice which were assigned to a control group (n=5) and two eribulin-treated groups (n=11). Mice in treatment groups were administered single-dose eribulin (0.3 or 1.0 mg/kg, i.p.) as on Day 1. Three days (Day 4) after eribulin treatment, the mice were injected with 18F-FMISO and pimonidazole (a hypoxia marker) 4 and 2 hours before sacrifice, respectively. One mouse from each group was imaged by small-animal PET 3 hour after eribulin treatment. Radioactivity in tissues was expressed as the percentage of injected dose per gram of tissue (%ID/g). Immunohistochemistry of pimonidazole and CD31 (a vascular marker) was also performed. Tumor size was measured on Days 1 and 4.
Results 18F-FMISO accumulation levels in the tumor were significantly decreased to 37 and 24% of the control value after 0.3 and 1 mg eribulin treatment, respectively [0.71 ± 0.23, 0.27 ± 0.12[asterisk] and 0.18 ± 0.05[asterisk] (%ID/g) for control, and 0.3 and 1 mg treatment; [asterisk]p < 0.001 vs control]. 18F-FMISO PET images also showed similar results (see Figure). As compared with the control, pimonidazole-positive areas were also significantly decreased to 28 and 8% of the control value after 0.3 and 1 mg eribulin treatment, respectively [8.7 ± 3.3, 2.5 ± 2.1[asterisk] and 0.7 ± 0.6[asterisk] (%positive area) for control, and 0.3 and 1 mg treatment; [asterisk]p < 0.001 vs control]. The number of microvessels in tumors increased after eribulin treatment. No significant changes in tumor size was observed between pre- and post-treatments with eribulin in all groups.
Conclusions In human breast cancer cell xenograft, 18F-FMISO accumulation levels in the tumor decreased dose-dependently with eribulin treatment, which was consistent with the decrease in pimonidazole-positive areas. Thus, we first demonstrated the elimination of tumor hypoxic conditions by eribulin treatment, indicating its antivascular activity and remodeling of tumor vasculature. $$graphic_E5B7346F-9537-403E-99AA-BBB091E279E3$$