Guadecitabine sodium|929904-85-8|安捷凯

Background

Guadecitabine is a novel hypomethylating dinucleotide of decitabine and deoxyguanosine that is resistant to degradation by cytidine deaminase. Guadecitabine Sodium is the easily dissolved form of Guadecitabine^[1].

Guadecitabine (0.1, 0.3, 1, 5μM, 48h) increased sensitivity to cisplatin for both the parental and the resistant A2780 cells. Although among other ovarian cancer cell lines, the parental A2780- cisplatin resistant cells is considered to be cisplatin “sensitive”, it has a relatively high IC50 for the drug^[2].

Guadecitabine (50nM-2μM, 24h) pretreatment synergistically interacted with ASTX660 to induce cell death in five AML cell lines (MOLM-13, ML-2, MV4-11, PLB-985, KG-1) with various genetic backgrounds and representing different AML subtypes?^[3].

Tumor-bearing immune-deficient mice were exposed subcutaneously to Guadecitabine at doses of 3, 6.1, or 10 mg/kg, daily for 5 days, with tumors harvested on day 7. Most mice treated on the 5 day schedule with 10mg/kg/day Guadecitabine died; all mice treated with 6.1mg/kg/day Guadecitabine developed gastrointestinal toxicity. Minimal toxicity was observed in mice treated with 3mg/kg/day. Guadecitabine treatment caused hypomethylation of?LINE-1?and?NY-ESO-1?at all doses^[4].

参考文献:
[1].Issa JJ, Roboz G, et al. Safety and tolerability of guadecitabine (SGI-110) in patients with myelodysplastic syndrome and acute myeloid leukaemia: a multicentre, randomised, dose-escalation phase 1 study. Lancet Oncol. 2015 Sep;16(9):1099-1110.
[2].Fang F, Munck J, et al. The novel, small-molecule DNA methylation inhibitor SGI-110 as an ovarian cancer chemosensitizer. Clin Cancer Res. 2014 Dec 15;20(24):6504-16.
[3].Dittmann J, Haydn T, et al. Next-generation hypomethylating agent SGI-110 primes acute myeloid leukemia cells to IAP antagonist by activating extrinsic and intrinsic apoptosis pathways. Cell Death Differ. 2020 Jun;27(6):1878-1895.
[4].rivastava P, Paluch BE, et al. Immunomodulatory action of SGI-110, a hypomethylating agent, in acute myeloid leukemia cells and xenografts. Leuk Res. 2014 Nov;38(11):1332-41.

Guadecitabine 是地西他滨和脱氧鸟苷的新型低甲基化二核苷酸,可抵抗胞苷脱氨酶的降解。 Guadecitabine Sodium 是 Guadecitabine 的易溶解形式^[1]。

Guadecitabine (0.1, 0.3, 1, 5μM, 48h) 增加了亲本细胞和耐药 A2780 细胞对顺铂的敏感性。尽管在其他卵巢癌细胞系中,亲本 A2780-顺铂耐药细胞被认为对顺铂"敏感",但其对该药物具有相对较高的 IC50^[2]。

Guadecitabine (50nM-2μM, 24h) 预处理与 ASTX660 协同作用,在具有不同遗传背景的五种 AML 细胞系（MOLM-13、ML-2、MV4-11、PLB-985、KG-1）中诱导细胞死亡并代表不同的 AML 子类型^[3]。

携带肿瘤的免疫缺陷小鼠皮下暴露于剂量为 3、6.1 或 10 mg/kg 的瓜地西他滨,持续 5 天,并在第 7 天收获肿瘤。大多数小鼠在 5 天的治疗方案中接受 10mg /kg/day 瓜地西他滨死亡；所有用 6.1mg/kg/天 Guadecitabine 治疗的小鼠都出现了胃肠道毒性。在用 3mg/kg/天处理的小鼠中观察到最小毒性。瓜地西他滨治疗导致所有剂量的 LINE-1 和 NY-ESO-1 低甲基化^[4]。

Protocol

Cell experiment [1]:

Cell lines

Leukemic cell lines(HL60, KG1a, U937)

Preparation Method

To evaluate the effect of Guadecitabine treatment on Cancer Testis Antigen methylation, HL60, U937, and KG1a leukemic cell lines were treated with Guadecitabine and harvested on day 5.

Reaction Conditions

Leukemic cell line were treated with Guadecitabine ( 0.1, 1.0 and 5μM) for 5 days.

Applications

Guadecitabine treatment resulted in significant reductions of?LINE-1?and?NY-ESO-1?promoter methylation in HL60, U937 and KG1a cells, as determined by quantitative bisulfite pyrosequencing.MAGE-A3/6?was also hypomethylated following Guadecitabine treatment in all cell lines.

Animal experiment [2]:

Animal models

SCID mice

Preparation Method

OVCAR3 cells were implanted into the hindquarters of SCID mice. After 2–3 weeks, when macroscopic tumors were formed, mice were treated with Guadecitabine?for 5day.

Dosage form

3 mg/kg/day, subcutaneous treatment

Applications

OVCAR3 tumors were treated with 3 mg/kg/d, 5 days Guadecitabine or vehicle control subcutaneously, 3?days later, injected with NY-ESO-1-specific CD8+ T-cells or vehicle control (PBS) intra-tumorally.?The combination of Guadecitabine and NY-ESO-1 specific T-cells showed delayed tumor growth in comparison with mice treated with Guadecitabine or NY-ESO-1-specific CD8 +T-cells alone.these data suggest Guadecitabine treatment enhances NY-ESO-1-specific antitumor responses?in vivo.

参考文献:

[1]. Srivastava P, Paluch BE,et al. Immunomodulatory action of SGI-110, a hypomethylating agent, in acute myeloid leukemia cells and xenografts. Leuk Res. 2014 Nov;38(11):1332-41.

[2]. Srivastava P, Paluch BE,et al. Immunomodulatory action of the DNA methyltransferase inhibitor SGI-110 in epithelial ovarian cancer cells and xenografts. Epigenetics. 2015;10(3):237-46.

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Guadecitabine sodium

Guadecitabine sodium详情

Background

Protocol

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