Hydroxycarbamide in combination with azacitidine or decitabine is antagonistic on DNA methylation inhibition
Hydroxycarbamide in combination with azacitidine or decitabine is antagonistic on DNA methylation inhibition
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DOI：
10.1111/j.1365-2141.2007.06707.x
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发表时间：
2007-09-01
影响因子：
6.5
通讯作者：
Yang, Allen S.
中科院分区：
文献类型：
--
作者：
Choi, Si Ho;Byun, Hyang-Min;Yang, Allen S.
阿扎胞苷和地西他滨是抑制DNA甲基化的胞苷类似物，用于治疗骨髓性血液恶性肿瘤。羟基脲（HC）（也称为羟基脲）是一种核糖核苷酸还原酶（RR）抑制剂，可阻断核糖核苷酸转化为脱氧核糖核苷酸，也用于治疗白血病和镰状细胞病。阿扎胞苷是一种核糖核苷，地西他滨是一种脱氧核糖核苷;因此，我们假设HC对RR的抑制作用与阿扎胞苷具有拮抗作用，与地西他滨具有协同作用。用阿扎胞苷或地西他滨联合HC处理HL-60和T24癌细胞系，并通过亚硫酸氢盐聚合酶链反应焦磷酸测序定量测量LRE 1、MAGEA 1和CDKN 2A的DNA甲基化。令人惊讶的是，我们发现HC阻断阿扎胞苷和地西他滨抑制DNA甲基化的能力，这种拮抗作用归因于HC诱导的细胞周期阻滞。然而，这种拮抗作用可以通过HC序贯治疗，随后使用阿扎胞苷或地西他滨来避免。该数据表明，HC的同时组合阻断阿扎胞苷和地西他滨抑制DNA甲基化的能力，因此这些药物应顺序使用。
Azacitidine and decitabine are cytidine analogues that inhibit DNA methylation, and are used to treat myeloid haematological malignancies. Hydroxycarbamide (HC) (also known as hydroxyurea), a ribonucleotide reductase (RR) inhibitor, blocks the conversion of ribonucleotides to deoxyribonucleotides, and is also used to treat leukaemia and sickle-cell disease. Azacitidine is a ribonucleoside and decitabine is a deoxyribonucleoside; therefore, we hypothesized that inhibition of RR by HC would be antagonistic to azacitidine and synergistic to decitabine. HL-60 and T24 cancer cell lines were treated with azacitidine or decitabine in combination with HC and DNA methylation of LRE1, MAGEA1 and CDKN2A was quantitatively measured by bisulphite-polymerase chain reaction pyrosequencing. Surprisingly, we found that HC blocked the ability of both azacitidine and decitabine to inhibit DNA methylation and this antagonistic effect was attributable to the arrest of the cell cycle induced by HC. However, this antagonism could be avoided with sequential treatment of HC followed by azacitidine or decitabine. This data suggest that concurrent combination of HC blocks the ability of azacitidine and decitabine to inhibit DNA methylation and therefore these drugs should be used sequentially.