Background
Decitabine(DAC) is a deoxycytidine analogue antimetabolite with oral bioactivity and functions as an inhibitor of DNA methyltransferase. By substituting for cytosine within DNA, Decitabine covalently captures DNA methyltransferases within the DNA structure, thereby inducing irreversible inhibition of this enzyme. Decitabine has been shown to be effective against multiple cancers, including chronic myelomonocytic leukaemia (CMML), acute myeloid leukaemia (AML) [1-3].
Decitabine (10 μM; 0-120hs) treatment significantly inhibited cell growth[4]. Decitabine-pretreated(low-dose:10 nM decitabine; 24h) CD8+ T cells have increased cytotoxicity against tumors following anti-PD-1 treatment[5]. Low-dose decitabine promoted the generation of Myeloid-derived suppressor cells (MDSCs) and enhanced their aerobic metabolism and immunosuppressive functions[6]. Decitabine treatment resulted in an increased CD4:CD8 T-cell ratio and an elevation in the central memory (Tcm, CD45RO + CD62L+) and CD25-positive populations among cultured CAR T cells when compared to CAR T cells[7].
Decitabine (1.0 mg/kg; i.p.; 5days) treatment inhibits tumorigenesis and leads to regression of established tumors in mice[8]. Decitabine (1.0 mg/kg, p.o) in combination with Tetrahydrouridine (THU) causes severe toxicity in female CD-1 mice, along with an elevated sensitivity to Decitabine toxicity correlated with Decitabine plasma levels [9].
参考文献:
[1]. Dhillon S. Decitabine/Cedazuridine: First Approval. Drugs. 2020 Sep;80(13):1373-1378. doi: 10.1007/s40265-020-01389-7. Erratum in: Drugs. 2021 Jan;81(1):179. PMID: 32860582; PMCID: PMC7708383.
[2]. Nakamura M, Nishikawa J, et,al ecitabine inhibits tumor cell proliferation and up-regulates e-cadherin expression in Epstein-Barr virus-associated gastric cancer. J Med Virol. 2017 Mar;89(3):508-517. doi: 10.1002/jmv.24634. Epub 2016 Nov 17. PMID: 27430892.
[3]. Parker WB. Enzymology of purine and pyrimidine antimetabolites used in the treatment of cancer. Chem Rev. 2009 Jul;109(7):2880-93. doi: 10.1021/cr900028p. PMID: 19476376; PMCID: PMC2827868.
[4]. Nakamura M, Nishikawa J, et,al Decitabine inhibits tumor cell proliferation and up-regulates e-cadherin expression in Epstein-Barr virus-associated gastric cancer. J Med Virol. 2017 Mar;89(3):508-517. doi: 10.1002/jmv.24634. Epub 2016 Nov 17. PMID: 27430892.
[5]. Han P, Hou Y, et,al. Low-dose decitabine modulates T-cell homeostasis and restores immune tolerance in immune thrombocytopenia. Blood. 2021 Aug 26;138(8):674-688. doi: 10.1182/blood.2020008477. PMID: 33876188; PMCID: PMC8394906.
[6]. Ni X, Wang L, et,al. Low-dose decitabine modulates myeloid-derived suppressor cell fitness via LKB1 in immune thrombocytopenia. Blood. 2022 Dec 29;140(26):2818-2834. doi: 10.1182/blood.2022016029. PMID: 36037415.
[7]. Wang Y, Tong C, et,al. Low-dose decitabine priming endows CAR T cells with enhanced and persistent antitumour potential via epigenetic reprogramming. Nat Commun. 2021 Jan 18;12(1):409. doi: 10.1038/s41467-020-20696-x. PMID: 33462245; PMCID: PMC7814040.
[8]. Wang LX, Mei ZY, et,al. Low dose decitabine treatment induces CD80 expression in cancer cells and stimulates tumor specific cytotoxic T lymphocyte responses. PLoS One. 2013 May 9;8(5):e62924. doi: 10.1371/journal.pone.0062924. PMID: 23671644; PMCID: PMC3650049.
[9]. Terse P, Engelke K, et,al. Subchronic oral toxicity study of decitabine in combination with tetrahydrouridine in CD-1 mice. Int J Toxicol. 2014 Mar-Apr;33(2):75-85. doi: 10.1177/1091581814524994. Epub 2014 Mar 17. PMID: 24639139; PMCID: PMC4001115.
地西他滨(Decitabine, DAC)是一种具有口服生物活性的脱氧胞苷类似物抗代谢物,具有DNA甲基转移酶抑制剂的功能。通过取代DNA内的胞嘧啶,Decitabine共价捕获DNA结构内的DNA甲基转移酶,从而诱导该酶的不可逆抑制。Decitabine已被证明对多种癌症有效,包括慢性髓细胞白血病(CMML)、急性髓细胞白血病(AML)[1-3]。
Decitabine (10 μM; 0-120hs) 处理显著抑制细胞生长[4]。Decitabine (low-dose:10 nM decitabine; 24h)预处理的CD8+ T细胞在抗PD-1治疗后对肿瘤的细胞毒性增加[5]。低剂量Decitabine促进髓源性抑制细胞的生成,增强其有氧代谢和免疫抑制功能[6]。与CAR - T细胞相比,Decitabine治疗导致培养的CAR - T细胞中CD4:CD8 T细胞比例升高,中枢记忆(Tcm, CD45RO + CD62L+)和CD25阳性群体升高[7]。
Decitabine治疗(1.0 mg/kg; i.p.; 5days)可抑制小鼠EL4细胞的肿瘤发生并导致已建立肿瘤的消退[8]。Decitabine(1.0 mg/kg, p.o)与四氢吡啶(THU)联用导致雌性 CD-1 小鼠发生严重毒性,并导致与 Decitabine 血浆水平相关的对 Decitabine 毒性的敏感性增加[9]。
Protocol
| Cell experiment [1]: |
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Cell lines
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SNU719, NCC24, and KATOIII cells
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Preparation Method
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Cells were seeded and cultured with only RPMI-1640 supplemented with FBS for 24 hr. After 24 hr of incubation, cells were treated in the presence or absence of Decitabine for 120 hr.
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Reaction Conditions
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10 μM; 0-120hs
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Applications
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Decitabine treatment significantly inhibited cell growth.
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| Animal experiment [2]: |
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Animal models
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C57BL/6 Mice
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Preparation Method
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Decitabine was dissolved in phosphate-buffered saline (PBS) (pH 7.4) to obtain 100 μM stocks and stored at 20℃. Mice with established EL4 tumors were injected with Decitabine (1.0 mg/kg body weight in 200 μl PBS) or PBS once daily for 5 consecutive days.
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Dosage form
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1.0 mg/kg; i.p.; 5days
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Applications
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Decitabine treatment inhibits tumorigenesis and leads to regression of established tumors in mice.
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参考文献:
[1]. Nakamura M, Nishikawa J,et,al. abine inhibits tumor cell proliferation and up-regulates e-cadherin expression in Epstein-Barr virus-associated gastric cancer. J Med Virol. 2017 Mar;89(3):508-517. doi: 10.1002/jmv.24634. Epub 2016 Nov 17. PMID: 27430892.
[2].Wang LX, Mei ZY, et,al ow dose decitabine treatment induces CD80 expression in cancer cells and stimulates tumor specific cytotoxic T lymphocyte responses. PLoS One. 2013 May 9;8(5):e62924. doi: 10.1371/journal.pone.0062924. PMID: 23671644; PMCID: PMC3650049.
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