Effects of 5-aza-2′-deoxycytidine on fetal hemoglobin levels, red cell adhesion, and hematopoietic differentiation in patients with sickle cell disease
- 1 December 2003
- journal article
- clinical trial
- Published by American Society of Hematology in Blood
- Vol. 102 (12) , 3865-3870
- https://doi.org/10.1182/blood-2003-05-1738
Abstract
Fetal hemoglobin (HbF) decreases polymerization of sickle hemoglobin (HbS) and improves outcomes in sickle cell disease (SSD). Therefore, a therapeutic goal in SSD is pharmacologic reactivation of HbF. Silencing of the γ-globin (HbF) gene is associated with DNA methylation. The cytosine analog 5-aza-2′-deoxycytidine (decitabine) hypomethylates DNA by inhibiting DNA methyltransferase. We examined if subcutaneous decitabine could increase HbF levels and improve SSD pathophysiology without cytotoxicity. Eight symptomatic SSD patients resistant or intolerant of standard treatment with hydroxyurea received decitabine 0.2 mg/kg subcutaneously 1 to 3 times per week in 2 cycles of 6-week duration. Treatment decreased neutrophils and increased mean HbF (6.5% to 20.4%, P < .0001) and mean total hemoglobin (76 to 96 g/L [7.6 to 9.6 g/dL], P < .001). Features of vaso-occlusive crisis pathophysiology such as red cell adhesion, endothelial damage, and coagulation pathway activity significantly improved. γ-Globin gene promoter methylation decreased, and platelets and the proportion of megakaryocytes and erythroid cells in the marrow increased without a decrease in marrow cellularity, consistent with a DNA hypomethylating, noncytotoxic mechanism of action. Weekly subcutaneous decitabine produces cumulative increases in HbF and total hemoglobin through a noncytotoxic mechanism of action. Chronic dosing and sustained increases in hemoglobin F and total hemoglobin levels may be possible. Further studies in SSD and thalassemia are indicated.Keywords
This publication has 30 references indexed in Scilit:
- Transcriptional accessibility for genes of multiple tissues and hematopoietic lineages is hierarchically controlled during early hematopoiesisBlood, 2003
- Pathogenesis and Treatment of Sickle Cell DiseaseNew England Journal of Medicine, 1997
- Effect of Hydroxyurea on the Frequency of Painful Crises in Sickle Cell AnemiaNew England Journal of Medicine, 1995
- Suppression of intestinal neoplasia by DNA hypomethylationCell, 1995
- Treatment with Azacitidine of Patients with End-Stage β-ThalassemiaNew England Journal of Medicine, 1993
- Fragile sites induced by 5-azacytidine and 5-azadeoxycytidine in the murine genomeHereditas, 1990
- Microvascular sites and characteristics of sickle cell adhesion to vascular endothelium in shear flow conditions: pathophysiological implications.Proceedings of the National Academy of Sciences, 1989
- [22] Secretion of thrombospondin from human blood plateletsPublished by Elsevier ,1989
- DNA methylation in the human γδβ-globin locus in erythroid and nonerythroid tissuesCell, 1980
- THE SIGNIFICANCE OF THE PAUCITY OF SICKLE CELLS IN NEWBORN NEGRO INFANTSThe Lancet Healthy Longevity, 1948