Influence of anticancer agents on cell survival, proliferation, and CD4+CD25+Foxp3+ regulatory T cell-frequency in human peripheral-blood mononuclear cells activated by T cell-mitogen.
Influence of anticancer agents on cell survival, proliferation, and CD4+CD25+Foxp3+ regulatory T cell-frequency in human peripheral-blood mononuclear cells activated by T cell-mitogen.
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DOI：
10.1016/j.intimp.2012.11.008
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发表时间：
2013
影响因子：
5.6
通讯作者：
N. Tohyama;Sachiko Tanaka;K. Onda;K. Sugiyama;T. Hirano
中科院分区：
文献类型：
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作者：
N. Tohyama;Sachiko Tanaka;K. Onda;K. Sugiyama;T. Hirano
目前使用的许多抗癌剂被认为不仅对癌细胞而且对功能性免疫细胞具有细胞毒性。为了了解更多关于化疗药物在癌症化疗中的免疫抑制不良影响，我们研究了三氧化二砷，达卡巴嗪，5-氟尿嘧啶和甲氨蝶呤对体外T细胞有丝分裂原激活的人外周血单个核细胞（PBMC）的存活，增殖，细胞因子产生和CD 4 + CD 25 + Foxp 3+调节性T（Treg）细胞频率的影响。三氧化二砷、达卡巴嗪和5-氟尿嘧啶在1-100μM时显著增加台盼蓝染色（死亡）细胞率，并抑制PBMC的丝裂原活化增殖（p<0.05）。当浓度超过0.05μM时，甲氨蝶呤还显着增加死亡细胞的百分比，并抑制有丝分裂原激活的PBMC增殖（p<0.01）。在5μM浓度下，三氧化二砷可显著抑制活化PBMC产生干扰素γ、白细胞介素（IL）-4、-6和-10（p<0.05）。相比之下，抗癌剂在浓度分别大于0.1μM（甲氨蝶呤）、5μM（三氧化二砷和5-氟尿嘧啶）和50μM（达卡巴嗪）时显著增加活化PBMC中Treg细胞频率（p<0.05）。在0.05-50μM浓度范围内，这些药物对活化PBMC转化生长因子（TGF）β的产生无显著影响。我们的数据表明，抗癌药物：三氧化二砷、达卡巴嗪、5-氟尿嘧啶和甲氨蝶呤不仅通过抑制T细胞的增殖反应，而且还通过增加Treg细胞的频率来减弱T细胞介导的免疫，这可能导致抑制效应T细胞功能。
Many anticancer agents currently used are considered to be cytotoxic not only to cancer cells but also to functional immune cells. To learn more about the immunosuppressive adverse influence of chemotherapeutic drugs in cancer chemotherapy, we examined the effects of arsenic trioxide, dacarbazine, 5-fluorouracil, and methotrexate on the survival, proliferation, cytokine production, and CD4+CD25+Foxp3+regulatory T (Treg) cell-frequency in human peripheral blood mononuclear cells (PBMCs) activated by T cell mitogen in vitro. Arsenic trioxide, dacarbazine, and 5-fluorouracil increased trypan-blue stained (dead) cell rates and suppressed the mitogen-activated proliferation of PBMCs significantly at 1–100μM (p<0.05). Methotrexate also significantly increased the percentages of dead cells and suppressed the mitogen-activated PBMC-proliferation at concentrations of more than 0.05μM (p<0.01). Arsenic trioxide significantly inhibited the production of interferon γ, interleukin (IL)-4, -6, and -10 from the activated PBMCs at 5μM (p<0.05). In contrast, the anticancer agents significantly increased Treg cell-frequency in the activated PBMCs at concentrations of more than 0.1μM for methotrexate, 5μM for arsenic trioxide and 5-fluorouracil, and 50μM for dacarbazine, respectively (p<0.05). These agents did not significantly influence the production of transforming growth factor (TGF) β from the activated PBMCs at a concentration range of 0.05–50μM. Our data suggest that the anticancer agents: arsenic trioxide, dacarbazine, 5-fluorouracil, and methotrexate attenuate T cell mediated immunity by not only inhibiting the proliferative response of T cells but by also increasing the frequency of Treg cells, which may result in the suppression of the effector T cell function.