5-氟尿嘧啶免疫调节作用研究进展
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摘要
5-氟尿嘧啶是一种氟化嘧啶类抗代谢药物.通过干扰肿瘤细胞DNA的复制合成发挥抗肿瘤作用。近年研究显示,5-氟尿嘧啶除抑制肿瘤细胞增殖外,对机体免疫系统功能亦有影响,文章对其作用通路及分子机制进行综述,分析其对T细胞、NK细胞、髓源抑制性细胞、炎性树突状细胞、外周血单个核细胞的影响,并对不同剂量5-氟尿嘧啶的免疫调节效应进行分析总结。
5-fluorouracil is a fluorinated pyrimidine anti-metabolite that exerts an anti-tumor effect by interfering with the replication and synthesis of tumor cell DNA. Recent studies have shown that in addition to inhibiting tumor cell proliferation, 5-fluorouracil also has an effect on the immune system function. The article reviews its pathway and molecular mechanism, and analyzes its T cell, NK cell, myeloid suppressor cell, and inflammatory. The influence of dendritic cells and peripheral blood mononuclear cells, and the immunomodulatory effects of different doses of S-fluorouracil were analyzed and summarized.
5-fluorouracil is a fluorinated pyrimidine anti-metabolite that exerts an anti-tumor effect by interfering with the replication and synthesis of tumor cell DNA. Recent studies have shown that in addition to inhibiting tumor cell proliferation, 5-fluorouracil also has an effect on the immune system function. The article reviews its pathway and molecular mechanism, and analyzes its T cell, NK cell, myeloid suppressor cell, and inflammatory. The influence of dendritic cells and peripheral blood mononuclear cells, and the immunomodulatory effects of different doses of S-fluorouracil were analyzed and summarized.
引文
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[22]夏丽玲,赵素莲,卫琴,等. 5-氟尿嘧啶对肝癌小鼠髓系抑制性细胞表达及功能的影响[J].中华微生物学和免疫学杂志,2014, 34(9):651-656. DOI:10. 3760/cma. j. issn. 0254-5101.2014.09.001.
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[24]张亚辉,赵林涛,朱波.肿瘤5-氟尿嘧啶治疗后可提高CD8+T细胞免疫应答[J].免疫学杂志,2014, 30(4):293-301. DOI:10.13431/j. cnki. immunol. j. 20140063.
[25] Reynolds G, Gibbon JR, Pratt AG, et al. Synovial CD4~+T-cell-derived GM-CSF supports the differentiation of an inflammatory dendritic cell population in rheumatoid arthritis[J]. Ann Rheum Dis,2016, 75(5):899-907. DOI:10. 1136/annrheumdis-2014-206578.
[26] Sequra E, Amigorena S. Inflammatory dendritic cells in mice and humans[J]. Trends Immunol, 2013, 34(9):440-445. DOI:10.1016/j. it. 2013.06.001.
[27]Poncini CV, González-Cappa SM. Dual role of monocyte-derived dendritic cells in Trypanosoma cruzi infection[J]. Eur J Immunol,2017,47(11):1936-1948. DOI:10.1002/eji.201646830.
[28] Plantinga M, Guilliams M, Vanheerswynghels M, et al. Conventional and monocyte-derived CDllb(+)dendritic cells initiate and maintain T helper 2 cell-mediated immunity to house dust mite allergen[J]. Immunity, 2013, 38(2):322-335. DOI:10.1016/j. immuni.2012.10.016.
[29] Eisenthal A, Eytan K, Brazowski E, et al. Effects of 5-fluorouracil on human mitogen-activated peripheral blood lymphocytes from healthy individuals[J]. Anticancer Res, 2008, 28(6A):3785-3791. DOI:10.1097/CAD-obo13e328312coe5.
[30] Li Y, Zhu S, Zhang Y, et al. High fat diet-induced obesity exacerbates hematopoiesis deficiency and cytopenia caused by 5-fluorouracil via peroxisome proliferator-activated receptorγ[J]. Exp Hematol,2018, 60:30-39. el. DOI:10.1016/j. exphem. 2017.12.013.
[31] Abedi-Valugerdi M, Wolfsberger.J, Pillai PR, et al. 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[J]. Int Immunopharmacol,2016,40:41-49. DOI:10.1016/j. intimp.2016.08.023.
[32] Namdar A, Mirzaei HR, Hafezi M, et al. Low Noncytotoxic Concentrations of 5-Fluorouracil Have No Adverse Effects on Maturation and Function of Bone Marrow-Derived Dendritic Cells in vitro:A Potentially Safe Adjuvant for Dendritic Cell-Based Cancer Therapy[J].Int Arch Allergy Immunol, 2015, 168(2):122-130. DOI:10.1159/000442290.
[2] Gu M, Li SY, Huang XE, et al. A phase II study on continuous infusional paclitaxel and 5-Fu as first-line chemotherapy for patients with advanced esophageal cancer[J]. Asian Pac J Cancer Prev,2012, 13(11):5587-5591. DOI:10.7314/APJCP.2012. 135587.
[3] Harbuzariu A, Gonzalez-Perez RR. Leptin-Notch axis impairs 5-fluorouracil effects on pancreatic cancer[J]. Oncolarget, 2018, 9(26):18239-18253. DOI:10.18632/oncotarget. 24435.
[4] Wang S, Zheng G, Tian S, et al. Echinacoside improves hematopoietic function in 5-FU-induced myelosuppression mice[J]. Life Sci,2015, 123:86-92. DOI:10. 1016/j. lfs.2015.01.002.
[5] Xiao H, Xiong L, Song X, et al. Angelica sinensis Polysaccharides Ameliorate Stress-Induced Premature Senescence of Hematopoietic Cell via Protecting Bone Marrow Stromal Cells from Oxidative Injuries Caused by 5-Fluorouracil[J]. Int J Mol Sci, 2017, 18(11):2265.DOI:10.3390/ijms18112265.
[6] Shaikh A, Bhartiya D, Kapoor S, et al. Delineating the effects of 5-fluorouracil and follicle-stimulating hormone on mouse bone marrow stem/progenitor cells[J]. Stem Cell Res Ther, 2016, 7(1):59.DOI:10.1186/s13287-016-0311-6.
[7] Ghiringhelli F, Apetoh L. Enhancing the Anticancer Effects of 5-Fluorouracil:Current Challenges and Future Perspectives[J]. Biomed J, 2015, 38(2):111-116. DOI:10.4103/2319-4170.130923.
[8] Marshall, HD, Kaech SM. Generating CD8 T cell heterogeneity:attack of the clones[J]. Immunity, 2013, 39(2):203-205. DOI:10.1016/j. immuni. 2013.08.008.
[9] Zhang L, Kaizuka Y, Hanagata N. Imaging of Fas-FasL membrane microdomains during apoptosis in a reconstituted cell-cell junction[J]. Biochem Biophys Res Commun, 2012, 422(2):298-304.DOI:10.1016/j.bbrc.2012.04.152.
[10] Khallouf H, Mrten A, Serba S, et al. Immunochemotherapy with 5-Fluorouracil and Interferon-αenhances the recognition of pancreatic cancer cells by NK and CD8~+T cells via increasing the expression of NKG2D ligands and MHC Class-I[J]. J Immunother, 2012, 35(3):245-253. DOI:10.1097/CJI.0b013e31824b3a76.
[11] Wu Y, Deng Z, Wang H, et al. Repeated cycles of 5-fluorouracil chemotherapy impaired anti-tumor functions of cytotoxic T cells in a CT26 tumor-bearing mouse model[J]. BMC Immunol, 2016, 17(1):29. DOI:10.1186/s12865-016-0167-7.
[12] Lin Y, Li Y, Ooi CP. 5-Fluorouracil encapsulated HA/PLGA composite microspheres for cancer therapy[J]. J Mater Sci Mater Med,2012, 23(10):2453-2460. DOI:10.1007/s10856-012-4723-2.
[13] Schouppe E, Mommer C, Movahedi K, et al. Tumor-induced myeloid-derived suppressor cell subsets exert either inhibitory or stimulatory effects on distinct CD8~+T-cell activation events[J]. Eur J Immunol, 2013, 43(11):2930-2942. DOI:10. 1002/eji.201343349.
[14] Ugel S, De Sanctis F, Mandruzzato S, et al. Tumor-induced myeloid deviation:when myeloid-derived suppressor cells meet tumor-associated macrophages[J]. J Clin Invest, 2015, 125(9):3365-3376. DOI:10.1172/JCI80006.
[15] Tcyganov E, Mastio J, Chen E, er al. Plasticity of myeloid-ferived suppressor cells in cancer[J]. Curr Opin Immunol, 2018, 51:76-82. DOI:10. 1016/j.coi.2018.03.009.
[16] Veglia F, Perego M, Gabrilovich D. Myeloid-derived suppressor cells coming of age[J]. Nat Immunol, 2018, 19(2):108-119.DOI:10.1038/s41590-017-0022-x.
[17] Woodland DL. Myeloid-Derived Suppressor Cells[J]. Viral Immunol, 2017, 30(2):81. DOI:10.1089/vim. 2017.29016. dlw.
[18] Arocena AR, Onofrio LI, Pellegrini AV, et al. Myeloid-derived suppressor cells are key players in the resolution of inflammation during a model of acute infection[J]. Eur J Immunol, 2014, 44(1):184-194. DOI:10.1002/eji.201343606.
[19] Qu P, Wang LZ, Lin PC. Expansion and functions of myeloid-derived suppressor cells in the tumor microenvironment[J]. Cancer Lett,2016, 380(1):253-256. DOI:10.1016/j.canlet.2015.10.022.
[20] Qu X, Felder MA, Perez Horta Z, et al. Antitumor effects of antiCD40/CpG immunotherapy combined with gemcitabine or 5-fluorouracil chemotherapy in the B16 melanoma model[J]. Int Immunopharmacol, 2013, 17(4):1141-1147. DOI:10. 1016/j. intimp.2013.10.019.
[21] Khosravianfar N, Hadjati J, Namdar A, et al. Myeloid-derived Suppressor Cells Elimination by 5-Fluorouracil Increased Dendritic Cellbased Vaccine Function and Improved Immunity in Tumor Mice[J].Iran J Allergy Asthma Immunol, 2018, 17(1):47-55.
[22]夏丽玲,赵素莲,卫琴,等. 5-氟尿嘧啶对肝癌小鼠髓系抑制性细胞表达及功能的影响[J].中华微生物学和免疫学杂志,2014, 34(9):651-656. DOI:10. 3760/cma. j. issn. 0254-5101.2014.09.001.
[23] Abedi-Valugerdi M, Zheng W, Benkessou F, et al. Differential effects of low-dose fludarabine or 5-fluorouracil on the tumor growth and myeloid derived immunosuppression status of tumor-bearing mice[J]. Int Immunopharmacol, 2017, 47:173-181. DOI:10.1016/j.intimp. 2017.04.006.
[24]张亚辉,赵林涛,朱波.肿瘤5-氟尿嘧啶治疗后可提高CD8+T细胞免疫应答[J].免疫学杂志,2014, 30(4):293-301. DOI:10.13431/j. cnki. immunol. j. 20140063.
[25] Reynolds G, Gibbon JR, Pratt AG, et al. Synovial CD4~+T-cell-derived GM-CSF supports the differentiation of an inflammatory dendritic cell population in rheumatoid arthritis[J]. Ann Rheum Dis,2016, 75(5):899-907. DOI:10. 1136/annrheumdis-2014-206578.
[26] Sequra E, Amigorena S. Inflammatory dendritic cells in mice and humans[J]. Trends Immunol, 2013, 34(9):440-445. DOI:10.1016/j. it. 2013.06.001.
[27]Poncini CV, González-Cappa SM. Dual role of monocyte-derived dendritic cells in Trypanosoma cruzi infection[J]. Eur J Immunol,2017,47(11):1936-1948. DOI:10.1002/eji.201646830.
[28] Plantinga M, Guilliams M, Vanheerswynghels M, et al. Conventional and monocyte-derived CDllb(+)dendritic cells initiate and maintain T helper 2 cell-mediated immunity to house dust mite allergen[J]. Immunity, 2013, 38(2):322-335. DOI:10.1016/j. immuni.2012.10.016.
[29] Eisenthal A, Eytan K, Brazowski E, et al. Effects of 5-fluorouracil on human mitogen-activated peripheral blood lymphocytes from healthy individuals[J]. Anticancer Res, 2008, 28(6A):3785-3791. DOI:10.1097/CAD-obo13e328312coe5.
[30] Li Y, Zhu S, Zhang Y, et al. High fat diet-induced obesity exacerbates hematopoiesis deficiency and cytopenia caused by 5-fluorouracil via peroxisome proliferator-activated receptorγ[J]. Exp Hematol,2018, 60:30-39. el. DOI:10.1016/j. exphem. 2017.12.013.
[31] Abedi-Valugerdi M, Wolfsberger.J, Pillai PR, et al. 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[J]. Int Immunopharmacol,2016,40:41-49. DOI:10.1016/j. intimp.2016.08.023.
[32] Namdar A, Mirzaei HR, Hafezi M, et al. Low Noncytotoxic Concentrations of 5-Fluorouracil Have No Adverse Effects on Maturation and Function of Bone Marrow-Derived Dendritic Cells in vitro:A Potentially Safe Adjuvant for Dendritic Cell-Based Cancer Therapy[J].Int Arch Allergy Immunol, 2015, 168(2):122-130. DOI:10.1159/000442290.