title: 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.
abstract: 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 17mg/kg, 50 and 100mg/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 60mg/kg) only reduced the number of circulating neutrophils, with no effects on these other parameters. At a concentration of 500mg/kg, Treo was ineffective, whereas, doses of 1500 and 3000mg/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.
authors: Experimental Cancer Medicine, Clinical Research Center, Novum, Karolinska Institutet, Huddinge, 141 86 Stockholm, Sweden. Electronic address: Manuchehr.Abedi-Valugerdi@ki.se.
authors: Manuchehr
authors: M
authors: Abedi-Valugerdi
authors: Experimental Cancer Medicine, Clinical Research Center, Novum, Karolinska Institutet, Huddinge, 141 86 Stockholm, Sweden. Electronic address: johanna.wolfsberger@ki.se.
authors: Johanna
authors: J
authors: Wolfsberger
authors: Experimental Cancer Medicine, Clinical Research Center, Novum, Karolinska Institutet, Huddinge, 141 86 Stockholm, Sweden. Electronic address: preethi.r.pillai@gmail.com.
authors: Preethi Raghuram
authors: PR
authors: Pillai
authors: Experimental Cancer Medicine, Clinical Research Center, Novum, Karolinska Institutet, Huddinge, 141 86 Stockholm, Sweden. Electronic address: wenyi.zheng@ki.se.
authors: Wenyi
authors: W
authors: Zheng
authors: Cancer Immunotherapy and Regenerative Medicine Research Group, Breast Cancer Research Center, Tehran, Iran. Electronic address: Behnam.Sadeghi@ki.se.
authors: Behnam
authors: B
authors: Sadeghi
authors: Experimental Cancer Medicine, Clinical Research Center, Novum, Karolinska Institutet, Huddinge, 141 86 Stockholm, Sweden. Electronic address: ying.zhao.1@ki.se.
authors: Ying
authors: Y
authors: Zhao
authors: Experimental Cancer Medicine, Clinical Research Center, Novum, Karolinska Institutet, Huddinge, 141 86 Stockholm, Sweden; Clinical Research Center, Karolinska University Hospital, Huddinge, 141 86 Stockholm, Sweden. Electronic address: Moustapha.Hassan@ki.se.
authors: Moustapha
authors: M
authors: Hassan
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology* / Q000627:therapeutic use; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use; D001854:Bone Marrow Cells / Q000166:cytology; D002066:Busulfan / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D004347:Drug Interactions; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology* / Q000627:therapeutic use; D007166:Immunosuppressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D007958:Leukocyte Count; D008223:Lymphoma / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000166:cytology / Q000187:drug effects*; D013154:Spleen / Q000166:cytology; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D000964:Antimetabolites, Antineoplastic; D018906:Antineoplastic Agents, Alkylating; D007166:Immunosuppressive Agents; C018404:treosulfan; D002066:Busulfan; D005472:Fluorouracil
keywords: 5-Fluorouracil; Busulfan; Granulocytic myeloid-derived suppressor cells; Myeloid-derived suppressor cells; Neutrophils; Treosulfan; Tumor; Wright's stain