DNA methyltransferase inhibitors - state of the art

被引:204
作者
Goffin, J [1 ]
Eisenhauer, E [1 ]
机构
[1] Queens Univ, Natl Canc Inst Canada, Clin Trials Grp, Kingston, ON K7L 3N6, Canada
关键词
DNA methylation; DNA methyltransferase antagonists; oligodeoxynucleotides; tumor suppressor genes;
D O I
10.1093/annonc/mdf314
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Background: DNA methylation is the addition of a methyl group to the 5 position of cytosine. It is an epigenetic process with several effects, including chromatin structure modulation, transcriptional repression and the suppression of transposable elements. In malignancy, methylation patterns change, resulting in global hypomethylation with regional hypermethylation. This can lead to genetic instability and the repression of tumor suppressor genes. Design: A review of the DNA methyltransferase inhibitor literature was conducted. Results: DNA methylation inhibitors have demonstrated the ability to inhibit hypermethylation, restore suppressor gene expression and exert antitumor effects in in vitro and in vivo laboratory models. Four inhibitors, which are analogs of the nucleoside deoxycitidine, have been clinically tested: 5-azacytidine, 5-aza-2'-deoxycytidine, 1-beta-D-arabinofuranosyl-5-azacytosine and dihydro-5-azacytidine. The first two have demonstrated encouraging antileukemic activity but little activity in solid tumors, while the latter two are no longer under study due to lack of efficacy. A fifth agent, MG98, is an antisense oligodeoxynucleotide directed against the 3' untranslated region of the DNA methyltransferase-1 enzyme mRNA, and is now under phase II study. Conclusions: While some positive clinical results with DNA methyltransferase inhibitors have been seen, a definitive clinical role for these agents will most likely require combination therapy, and good phase III studies are needed.
引用
收藏
页码:1699 / 1716
页数:18
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