Suppressive effects of low-dose 5-fluorouracil, busulfan or treosulfan on the expansion of circulatory neutrophils and myeloid derived immunosuppressor cells in tumor-bearing mice

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As reported previously, large numbers of neutrophils appear in the circulation during tumor development. However, the relationship between these cells and myeloid-derived suppressor cells (MDSCs), as well as their susceptibility to myelosuppressive drugs have not been yet investigated. Here, we employed a lymphoma model to characterize tumor-associated circulating neutrophils, including their sensitivity to 5-fluorouracil (5-FU), busulfan (Bu) or treosulfan (Treo). Tumor-bearing mice exhibited pronounced elevations in the numbers of splenic MDSCs and circulating neutrophils, MDSCs, and granulocytic-MDSCs (G-MDSCs). Although these cells were not affected by 5-FU at a dose of 17 mg/kg, 50 and 100 mg/kg were equally effective in causing dramatic tumor regression, normalizing neutrophil number, and significantly reducing the numbers of splenic MDSCs, B cells, and bone marrow myeloid cells. Treatment with Bu (10, 30 or 60 mg/kg) only reduced the number of circulating neutrophils, with no effects on these other parameters. At a concentration of 500 mg/kg, Treo was ineffective, whereas, doses of 1500 and 3000 mg/kg comparably reduced the tumor size as well as the numbers of circulatory neutrophils and bone marrow myeloid cells. Finally, in comparison to 5-FU alone, a combined treatment with low-dose 5-FU and Treo resulted in a more pronounced reduction in the numbers of circulatory neutrophils and bone marrow myeloid cells, together with longer survival time. We conclude that tumor-associated circulatory neutrophils represent blood MDSCs/G-MDSCs that are highly sensitive to 5-FU and Treo, but not Bu. Moreover, the efficacy of 5-FU can be potentiated by Treo.

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