Decitabine - Bedside to bench

被引:127
作者
Oki, Yasuhiro [1 ]
Aoki, Etsuko [1 ]
Issa, Jean-Pierre J. [1 ]
机构
[1] Univ Texas, MD Anderson Canc Ctr, Dept Leukemia, Houston, TX 77030 USA
关键词
decitabine; DNA methylation; DNA methyltransferase; translational research; hematologic malignancies; myelodysplastic syndrome; leukemia; CHRONIC MYELOGENOUS LEUKEMIA; LOW-DOSE 5-AZA-2'-DEOXYCYTIDINE; DNA METHYLTRANSFERASE EXPRESSION; HISTONE DEACETYLASE INHIBITION; ACUTE LYMPHOBLASTIC-LEUKEMIA; ACUTE MYELOID LEUKEMIAS; MYELODYSPLASTIC SYNDROMES; COLON-CANCER; HEMATOPOIETIC MALIGNANCIES; PROMOTER HYPERMETHYLATION;
D O I
10.1016/j.critrevonc.2006.07.010
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Purpose of the review: Epigenetic changes marked by DNA methylation are known to contribute to the malignant transformation of cells by silencing critical genes. Decitabine inhibits DNA methyltransferase and has shown therapeutic effects in patients with hematologic malignancies. However, the connection between the clinical activity of decitabine and its demethylating activity is not clear. Herein, we summarize the results of recent clinical trials of decitabine in hematologic malignancies, and review the translational research into decitabine's mechanism of clinical activity. Recent findings: Low-dose decitabine has been studied recently in multiple clinical trials and has been shown to be effective for treatment of myelodysplastic syndromes. Correlative laboratory studies of clinical trials have shown that decitabine induces global hypomethylation as well as hypomethylation of gene-specific promoters and activation of gene expression. Past a given threshold, induction of higher degrees of hypomethylation is not directly associated with a better clinical outcome. Moreover, studies have suggested that patients with promoter hypermethylation of p15(INK4B) at baseline have paradoxically a lower chance of achieving response than those without hypermethylation. Furthermore, several other genes activated by decitabine were independent of hypomethylation in the promoter regions. Conclusion: While at least part of decitabine's activity is through induction of hypomethylation and reactivation of critical genes, mechanisms independent from hypomethylation are also important for decitabine's antitumor activity. (c) 2006 Elsevier Ireland Ltd. All rights reserved.
引用
收藏
页码:140 / 152
页数:13
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