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].
References:
[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]。