生物活性

• 描述The DNA methyltransferase (DNMT) family are enzymes that can catalyze the transfer of methyl group to DNA using S-adenosylmethionine (SAM) as a methyl donor with subsequent conversion of SAM to S-adenosylhomocysteine (SAH). Inhibiting the DNMTs have shown particular promise in the treatment of haematological malignancies^[1]. Thioguanine which is used for the therapy of acute leukemia could inhibit the DNMT1.
  On both canine large T cell leukemia line CLGL-90 and B cell line CLL 17-7, after incubating with thioguanine at 1.5, 3.0 and 6.0 μM for 24 hours, DNMT1 expression measured was reduced. Global methylation also demonstrated significant decreases following treatment of 6.0 μM thioguanine^[2]. Similar results could be seen on Jurkat T cells. When the cells were treated with 1 - 3 μM of thioguanine for 24 hours, the percentage of cytosine methylation showed a decrease from 3.92% to 3.39% with 3 μM of thioguanine^[3].
  In VC8 cells injected CD1 nude mice cancer model, 1.5 mg/kg of thioguanine was administered i.p. daily for ten days. The tumor growth was significantly delayed after the treatment of thioguanine^[4].
• 作用机制After exposing to thioguanine, the DNMT1 is shifted toward ubiquination-mediated proteasomal degradation via alteration of the expression of histone lysine-specific demethylase^[2].

• 动物研究
  剂量	Mice: 5 mg/kg, 10 mg/kg[5] (i.p.)
  给药途径	i.p.

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT03334266	Obesity Infan... more >>t Obesity Mother-Child Relations Dietary Habits Breast Feeding Physical Activity Childhood Obesity Feeding Behavior Collapse <<	Not Applicable	Recruiting	December 31, 2021	United States, Arizona ... more >> Johns Hopkins Center for American Indian Health Recruiting Fort Defiance, Arizona, United States, 86504 Contact: Allison Barlow, PhD    410-955-6931    abarlow@jhu.edu    Contact: Nicole Neault, MPH    5057973309    nneault@jhu.edu    Johns Hopkins Center for American Indian Health Recruiting Whiteriver, Arizona, United States, 85941 Contact: Allison Barlow, PhD    410-955-6931    abarlow@jhu.edu    Contact: Nicole Neault, MPH    5057973309    nneault@jhu.edu    United States, New Mexico Johns Hopkins Center for American Indian Health Recruiting Shiprock, New Mexico, United States, 87420 Contact: Allison Barlow, PhD    410-955-6931    abarlow@jhu.edu    Contact: Nicole Neault, MPH    5057973309    nneault@jhu.edu Collapse <<
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  NCT02046694	Acute Lymphoblastic Leukemia (... more >>ALL) Collapse <<	Early Phase 1	Recruiting	September 2021	United States, Maryland ... more >> Johns Hopkins Hospital Recruiting Baltimore, Maryland, United States, 21287 Principal Investigator: Colleen Annesley, MD          Sub-Investigator: Patrick A Brown, MD          United States, Texas Texas Children's Cancer and Hematology Centers Recruiting Houston, Texas, United States, 77030 Contact: Julie Brackett, MD    832-822-4242       Sub-Investigator: Edward Sisson, MD          Principal Investigator: Julie Brackett, MD          United States, Washington Seattle Children's Hospital Recruiting Seattle, Washington, United States, 98105 Contact: Colleen Annesley, MD          Principal Investigator: Colleen Annesley, MD Collapse <<

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• 参考文献

• [1] Hogarth LA, Redfern CP, et al. The effect of thiopurine drugs on DNA methylation in relation to TPMT expression. Biochem Pharmacol. 2008;76(8):1024-35.

  [2] Flesner BK, Kumar SR, et al. 6-Thioguanine and zebularine down-regulate DNMT1 and globally demethylate canine malignant lymphoid cells. BMC Vet Res. 2014.

  [3] Wang H, Wang Y. 6-Thioguanine perturbs cytosine methylation at the CpG dinucleotide site by DNA methyltransferases in vitro and acts as a DNA demethylating agent in vivo. Biochemistry. 2009;48(10):2290-9.

  [4] Issaeva N, Thomas HD, et al. 6-thioguanine selectively kills BRCA2-defective tumors and overcomes PARP inhibitor resistance. Cancer Res. 2010;70(15):6268-76.