Eribulin improves tumor oxygenation demonstrated by ¹⁸F-DiFA hypoxia imaging, leading to radio-sensitization in human cancer xenograft models.

Abstract

Eribulin, an inhibitor of microtubule dynamics, is known to show antitumor effects through its remodeling activity in the tumor vasculature. However, the extent to which the improvement of tumor hypoxia by eribulin affects radio-sensitivity remains unclear. We utilized 1-(2,2-dihydroxymethyl-3-¹⁸F-fluoropropyl)-2-nitroimidazole (¹⁸F-DiFA), a new PET probe for hypoxia, to investigate the effects of eribulin on tumor hypoxia and evaluate the radio-sensitivity during eribulin treatment. Mice bearing human breast cancer MDA-MB-231 cells or human lung cancer NCI-H1975 cells were administered a single dose of eribulin. After administration, mice were injected with ¹⁸F-DiFA and pimonidazole, and tumor hypoxia regions were analyzed. For the group that received combined treatment with radiation, ¹⁸F-DiFA PET/CT imaging was performed before tumors were locally X-irradiated. Tumor size was measured every other day after irradiation. Eribulin significantly reduced ¹⁸F-DiFA accumulation levels in a dose-dependent manner. Furthermore, the reduction in ¹⁸F-DiFA accumulation levels by eribulin was most significant 7 days after treatment. These results were also supported by reduction of the pimonidazole-positive hypoxic region. The combined treatment showed significant retardation of tumor growth in comparison with the control, radiation-alone, and drug-alone groups. Importantly, tumor growth after irradiation was inversely correlated with ¹⁸F-DiFA accumulation. These results demonstrated that ¹⁸F-DiFA PET/CT clearly detected eribulin-induced tumor oxygenation and that eribulin efficiently enhanced the antitumor activity of radiation by improving tumor oxygenation.