Abstract:
:DNA methylation provides a major epigenetic code (besides histone modification) of the lineage- and development-specific genes (such as regulators of differentiation in the hematopoietic lineages) that control expression of normal cells. However, DNA methylation is also involved in malignancies because aberrant methylating gene activity occurs during leukemic transformation. Thus, genes such as tumor suppressor genes, growth-regulatory genes, and adhesion molecules are often silenced in various hematopoietic malignancies by epigenetic inactivation via DNA hypermethylation. This inactivation is frequently seen not only in transformed cell lines but also in primary leukemia cells. Because this defect is amenable to reversion by pharmacologic means, agents that inhibit DNA methylation have been developed to specifically target this hypermethylation defect in leukemia and preleukemia cases. The most clinically advanced agents, the azanucleosides 5-azacytidine and 5-aza-2'-deoxycytidine (decitabine), were discovered more than 25 years ago, when their methylation-inhibitory activities, even at low concentrations, became apparent. Although both of these agents, like cytarabine, had been clinically used until then at high doses, the redevelopment of these agents for low-dose schedules has revealed very interesting clinical activities for treating myelodysplasia (MDS) and acute myeloid leukemia (AML). Because these diseases occur mostly in patients over 60 years of age, low-dose schedules with these compounds provide a very promising approach in such patient groups by virtue of their low nonhematologic toxicity profiles. In the present review, we describe the development of treatments that target DNA hypermethylation in MDS and AML, and clinical results are presented. In addition, pharmacologic DNA demethylation may be viewed as a platform for biological modification of malignant cells to become sensitized (or resensitized) to secondary signals, such as differentiating signals (retinoids, vitamin D3) and hormonal signals (eg, estrogen receptor in breast cancer cells, androgen receptor in prostate cancer cells). Finally, an in vitro synergism between the reactivating potency of demethylating agents and inhibitors of histone deacetylation has been tested in several pilot studies of AML and MDS treatment. Finally, gene reactivation by either group of compounds results in therapeutically meaningful reactivation of fetal hemoglobin in patients with severe hemoglobinopathies, extending the therapeutic range of derepressive epigenetic agents to nonmalignant hematopoietic disorders.
journal_name
Int J Hematoljournal_title
International journal of hematologyauthors
Rüter B,Wijermans PW,Lübbert Mdoi
10.1532/ijh97.04094subject
Has Abstractpub_date
2004-08-01 00:00:00pages
128-35issue
2eissn
0925-5710issn
1865-3774journal_volume
80pub_type
杂志文章,评审abstract::The XCIND syndrome is named after distinct hypersensitivity to ionizing (X-ray) irradiation, cancer susceptibility, immunodeficiency, neurological abnormality, and double-strand DNA breakage. The disorders comprising XCIND syndrome are usually inherited in an autosomal recessive manner. Ataxia telangiectasia (A-T) is ...
journal_title:International journal of hematology
pub_type: 杂志文章,评审
doi:10.1007/s12185-012-1240-5
更新日期:2013-01-01 00:00:00
abstract::At present, the only 2 treatments that can prolong survival in patients with myelodysplastic syndrome (MDS) are allogeneic stem cell transplantation and intensive chemotherapy. Alternatives to myeloablative or conventional chemotherapy include: (1) supportive therapy, (2) stimulation of normal residual hematopoietic p...
journal_title:International journal of hematology
pub_type: 杂志文章,评审
doi:
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journal_title:International journal of hematology
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更新日期:1996-07-01 00:00:00
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journal_title:International journal of hematology
pub_type: 杂志文章,评审
doi:10.1007/BF02982650
更新日期:2003-05-01 00:00:00
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journal_title:International journal of hematology
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doi:10.1007/s12185-020-02834-9
更新日期:2020-06-01 00:00:00
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journal_title:International journal of hematology
pub_type: 杂志文章,评审
doi:10.1007/BF02982574
更新日期:2002-08-01 00:00:00
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journal_title:International journal of hematology
pub_type: 杂志文章
doi:10.1007/s12185-013-1483-9
更新日期:2014-01-01 00:00:00
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journal_title:International journal of hematology
pub_type: 临床试验,杂志文章,多中心研究
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更新日期:2017-10-01 00:00:00
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journal_title:International journal of hematology
pub_type: 杂志文章,评审
doi:10.1007/s12185-008-0118-z
更新日期:2008-07-01 00:00:00
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journal_title:International journal of hematology
pub_type: 杂志文章,评审
doi:10.1007/BF02983991
更新日期:2005-01-01 00:00:00
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journal_title:International journal of hematology
pub_type: 杂志文章
doi:10.1007/s12185-018-2437-z
更新日期:2018-07-01 00:00:00
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journal_title:International journal of hematology
pub_type: 杂志文章
doi:10.1007/s12185-017-2382-2
更新日期:2018-06-01 00:00:00
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journal_title:International journal of hematology
pub_type: 杂志文章
doi:10.1007/s12185-009-0324-3
更新日期:2009-06-01 00:00:00
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journal_title:International journal of hematology
pub_type: 信件
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更新日期:2020-08-01 00:00:00
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journal_title:International journal of hematology
pub_type: 杂志文章
doi:10.1532/IJH97.06227
更新日期:2007-05-01 00:00:00
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journal_title:International journal of hematology
pub_type: 杂志文章
doi:10.1007/s12185-019-02798-5
更新日期:2020-03-01 00:00:00
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journal_title:International journal of hematology
pub_type: 杂志文章
doi:10.1007/s12185-013-1350-8
更新日期:2013-07-01 00:00:00
abstract:BACKGROUND:The chronic myeloproliferative diseases (CMPDs) include chronic myelogenous leukemia (CML), primary (essential) thrombocythemia (PT), agnogenic myeloid metaplasia (AMM), and polycythemia vera (PV). Certain hematological malignancies have a different prevalence in our country than in countries with Caucasian ...
journal_title:International journal of hematology
pub_type: 杂志文章
doi:10.1007/BF02982113
更新日期:2002-06-01 00:00:00
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journal_title:International journal of hematology
pub_type: 杂志文章
doi:10.1007/s12185-009-0459-2
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pub_type: 杂志文章,评审
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journal_title:International journal of hematology
pub_type: 杂志文章
doi:
更新日期:1999-12-01 00:00:00
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pub_type: 杂志文章
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更新日期:2016-02-01 00:00:00
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pub_type: 杂志文章
doi:10.1007/s12185-012-1147-1
更新日期:2012-09-01 00:00:00
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journal_title:International journal of hematology
pub_type: 杂志文章
doi:10.1016/s0925-5710(97)00042-x
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journal_title:International journal of hematology
pub_type: 杂志文章
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更新日期:2009-05-01 00:00:00
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journal_title:International journal of hematology
pub_type: 杂志文章
doi:10.1532/IJH97.07054
更新日期:2007-10-01 00:00:00
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