Tetrahydrouridine (THU) is a nucleoside compound that can inhibit the activity of Cytidine Deaminase (CDA), with a Ki of 54nM[1]. Tetrahydrouridine can reduce the levels of uridine and deoxyuridine, thereby regulating nucleotide metabolism[2]. Tetrahydrouridine is commonly used in studies analyzing cell cycle regulation mechanisms and DNA damage response mechanisms[3]. Tetrahydrouridine is also used in research exploring the mechanisms of cancer development[4].
In vitro, treatment of MIAPaCa-2, H441, and H1299 cell lines with Tetrahydrouridine (100μM) alone for 3 days significantly inhibits cell proliferation while reducing E2F1 protein levels and increasing the proportion of cells in the G1 phase[5]. Co-treatment of NAT1 knockout (KO) MDA-MB-231 breast cancer cells with Tetrahydrouridine (60μM) and 5-formyl-2'-deoxycytidine (5fdC; 4 or 40μM) for 3 days significantly inhibits Cytidine Deaminase activation and cytotoxicity induced by 5fdC[6].
In vivo, a combination of Tetrahydrouridine (4mg/kg) and Decitabine (0.2mg/kg) administered subcutaneously to C57BL/6 mice bearing melanoma xenografts twice a week. Tetrahydrouridine extends the in vivo retention time of Decitabine by inhibiting Cytidine Deaminase (CDA) activity, thereby enhancing the inhibitory effect on melanoma[7]. A combination of Tetrahydrouridine (10mg/kg) and Decitabine (0.1mg/kg and 1mg/kg) administered subcutaneously twice a week to C57BL/6 mice bearing ovarian cancer xenografts. Tetrahydrouridine enhances the inhibitory effect of Decitabine on ovarian cancer, significantly prolonging mouse survival and reducing tumor burden[8].
References:
[1] Xiang TX, Niemi R, Bummer P, et al. Epimer interconversion, isomerization, and hydrolysis of tetrahydrouridine: implications for cytidine deaminase inhibition. J Pharm Sci. 2003 Oct;92(10):2027-39.
[2] Camiener GW. Studies of the enzymatic deamination of ara-cytidine. V. inhibition in vitro and in vivo by tetrahydrouridine and other reduced pyrimidine nucleosides. Biochem Pharmacol. 1968 Sep;17(9):1981-91.
[3] Rijkers GT, Zegers BJ, Spaapen LJ, et al. Purine nucleoside phosphorylase (PNP) deficiency leading to accumulation of lymphocytes in S-phase. Pediatr Hematol Oncol. 1986;3(4):353-9.
[4] Hill B, Jagadeesh D, Pohlman B, et al. A pilot clinical trial of oral tetrahydrouridine/decitabine for noncytotoxic epigenetic therapy of chemoresistant lymphoid malignancies. Semin Hematol. 2021 Jan;58(1):35-44.
[5] Funamizu N, Lacy CR, Fujita K, et al. Tetrahydrouridine inhibits cell proliferation through cell cycle regulation regardless of cytidine deaminase expression levels. PLoS One. 2012;7(5):e37424.
[6] Hong KU, Tagnedji AH, Doll MA, et al. Upregulation of cytidine deaminase in NAT1 knockout breast cancer cells. J Cancer Res Clin Oncol. 2023 Jul;149(8):5047-5060.
[7] Alcazar O, Achberger S, Aldrich W, et al. Epigenetic regulation by decitabine of melanoma differentiation in vitro and in vivo. Int J Cancer. 2012 Jul 1;131(1):18-29.
[8] Gomez S, Cox OL, Walker RR 3rd, et al. Inhibiting DNA methylation and RNA editing upregulates immunogenic RNA to transform the tumor microenvironment and prolong survival in ovarian cancer. J Immunother Cancer. 2022 Nov;10(11):e004974.
Tetrahydrouridine (THU)是一种核苷类化合物，能够抑制Cytidine Deaminase（CDA）的活性，Ki=54nM[1]。Tetrahydrouridine可降低尿苷和脱氧尿苷的水平，从而调节核苷酸代谢过程[2]。Tetrahydrouridine常被用于分析细胞周期调控机制以及DNA损伤响应机制的相关研究[3]。Tetrahydrouridine还被用于探索癌症发展机制的研究中[4]。
在体外，Tetrahydrouridine（100μM）单独处理MIAPaCa-2、H441和H1299细胞系3天，显著抑制细胞增殖，同时通过降低E2F1蛋白水平，增加G1期细胞比例[5]。Tetrahydrouridine（60μM）与5-甲酰基-2'-脱氧胞嘧啶（5fdC；4或40μM）共处理NAT1基因敲除（KO）的MDA-MB-231乳腺癌细胞3天，Tetrahydrouridine显著抑制了5fdC诱导的Cytidine Deaminase激活和细胞毒性[6]。
在体内，Tetrahydrouridine（4mg/kg）与Decitabine（0.2mg/kg）联合皮下注射于黑色素瘤异种移植C57BL/6小鼠，每周两次。Tetrahydrouridine通过抑制Cytidine Deaminase（CDA）活性，延长Decitabine的体内滞留时间，增强对黑色素瘤的抑制作用[7]。Tetrahydrouridine（10mg/kg）联合Decitabine（0.1mg/kg和1mg/kg）每周两次皮下注射，用于处理8卵巢癌异种移植C57BL/6小鼠。Tetrahydrouridine增强Decitabine对卵巢癌的抑制作用，显著延长小鼠生存期并减少肿瘤负荷[8]。