Oral decitabine reactivates expression of the methylated γ-globin gene in Papio anubis
Oral decitabine reactivates expression of the methylated γ-globin gene in Papio anubis
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DOI：
10.1002/ajh.21020
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发表时间：
2007-11-01
影响因子：
12.8
通讯作者：
DeSimone, Joseph
中科院分区：
文献类型：
--
作者：
Lavelle, Donald;Chin, Janet;DeSimone, Joseph
与启动子区域的DNA甲基化增加相关的肿瘤抑制基因的沉默在许多形式的癌症中是经常观察到的。使用DNA甲基转移酶的药理学抑制剂如5-氮杂-2 '-脱氧胞苷（地西他滨）重新激活这些基因是值得的治疗目标。低剂量静脉注射和皮下注射地西他滨方案对狒狒和镰状细胞病患者甲基化y-珠蛋白基因去甲基化和重新激活表达的有效性和耐受性导致了该药物低剂量方案在骨髓增生异常综合征患者中的成功试验。由于这些低剂量方案耐受性良好且毒性最小，因此它们适合于长期给药以维持启动子低甲基化和靶基因的表达。使用DNA甲基转移酶抑制剂的口服给药疗法的开发将促进这种慢性治疗方法。我们测试了地西他滨和一种新的盐衍生物，甲磺酸地西他滨，口服给药时重新激活狒狒甲基化y-珠蛋白基因的能力。我们的研究结果表明，口服这些药物的剂量17-34倍的最佳皮下剂量的地西他滨重新激活胎儿血红蛋白，去甲基化的β-和γ-珠蛋白基因启动子，并增加组蛋白乙酰化这些启动子在狒狒（Papio anubis）。
The silencing of tumor suppressor genes associated with increased DNA methylation of the promoter regions is a frequent observation in many forms of cancer. Reactivation of these genes using pharmacological inhibitors of DNA methyltransferase such as 5-aza-2'-deoxycytidine (decitabine) is a worthwhile therapeutic goal. The effectiveness and tolerability of low-dose intravenous and subcutaneous decitabine regimens to demethylate and reactivate expression of the methylated y-globin gene in baboons and in patients with sickle cell disease led to successful trials of low-dose regimens of this drug in patients with myelodysplastic syndrome. Since these low-dose regimens are well-tolerated with minimal toxicity, they are suitable for chronic dosing to maintain promoter hypomethylation and expression of target genes. The development of an orally administered therapy using DNA methyltransferase inhibitors would facilitate such chronic approaches to therapy. We tested the ability of decitabine and a new salt derivative, decitabine mesylate, to reactivate the methylated y-globin gene in baboons when administered orally. Our results demonstrate that oral administration of these drugs at doses 17-34 times optimal subcutaneous doses of decitabine reactivates fetal hemoglobin, demethylates the epsilon- and y-globin gene promoters, and increases histone acetylation of these promoters in baboons (Papio anubis).