Delivery of 5-aza-2′-deoxycytidine to cells using oligodeoxynucleotides
Delivery of 5-aza-2′-deoxycytidine to cells using oligodeoxynucleotides
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DOI：
10.1158/0008-5472.can-07-0251
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发表时间：
2007-07-01
期刊：
影响因子：
11.2
通讯作者：
Jones, Peter A.
中科院分区：
文献类型：
--
作者：
Yoo, Christine B.;Jeong, Shinwu;Jones, Peter A.
表观遗传学治疗的主要目标是通过使用染色质修饰药物来逆转异常的启动子甲基化，恢复肿瘤抑制基因的正常功能。地西他滨，或5-氮杂-2‘-脱氧胞苷(5-aza-2’-deoxcytidine，5-aza-cdr)，是一种具有良好特性的药物，现在已被食品和药物管理局批准用于治疗骨髓增生异常综合征。虽然5-氮杂-CDR是一种非常有效的DNA甲基化抑制剂，但它容易被胞苷脱氨酶降解和水解性裂解。我们发现含有5-aza-cdr的短寡核苷酸在与5-aza-cdr相当的浓度下也可以抑制癌细胞中的DNA甲基化。对二核苷酸S110的详细研究表明，在将其氮杂部分掺入DNA后，它通过类似于5-氮杂-CDR的机制发挥作用。在S110二核苷酸中，三氮杂环在水溶液中的稳定性没有提高，但胞苷脱氨酶的脱氨基作用显著降低。这是首次证明使用短寡核苷酸来提供核苷酸药物的有效传递和细胞摄取和保护。从酶的降解。这种方法可能会为更稳定和更有效的DNA甲基化抑制剂铺平道路，并为改进现有的治疗方法提供手段。
The major goal of epigenetic therapy is to reverse aberrant promoter hypermethylation and restore normal function of tumor suppressor genes by the use of chromatin-modifying drugs. Decitabine, or 5-aza-2 '-deoxycytidine (5-aza-CdR), is a well-characterized drug that is now Food and Drug Administration approved for the treatment of myelodysplastic syndrome. Although 5-aza-CdR is an extremely potent inhibitor of DNA methylation, it is subject to degradation by hydrolytic cleavage and deamination by cytidine deaminase. We show that short oligonucleotides containing a 5-aza-CdR can also inhibit DNA methylation in cancer cells at concentrations comparable with 5-aza-CdR. Detailed studies with S110, a dinucleotide, showed that it works via a mechanism similar to that of 5-aza-CdR after incorporation of its aza-moiety into DNA. Stability of the triazine ring in aqueous solution was not improved in the S110 dinucleotide; however, deamination by cytidine deaminase was dramatically decreased. This is the first demonstration of the use of short oligonucleotides to provide effective delivery and cellular uptake of a nucleotide drug and protection. from enzymatic degradation. This approach may pave the way for more stable and potent inhibitors of DNA methylation as well as provide means for improving existing therapeutics.