Effects of 5-aza-2'-deoxycytidine on fetal hemoglobin levels, red cell adhesion, and hematopoietic differentiation in patients with sickle cell disease
| Autor: | Yogen Saunthararajah, Yi Hsiang Chen, Linda R. Bressler, Joseph DeSimone, Cheryl A. Hillery, Robert E. Molokie, Louise Dorn, Don Lavelle, Stefana Gavazova, Ronald Hoffman |
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| Rok vydání: | 2003 |
| Předmět: |
Hemolytic anemia
Adult Male Erythrocytes Thalassemia Immunology Decitabine Anemia Sickle Cell Pharmacology Biochemistry Bone Marrow hemic and lymphatic diseases Fetal hemoglobin medicine Cell Adhesion Humans Vascular Diseases Blood Coagulation Cytosine analog Fetal Hemoglobin Inflammation business.industry Cell Differentiation Cell Biology Hematology DNA Methylation Middle Aged medicine.disease Hematopoiesis Red blood cell medicine.anatomical_structure Hemoglobinopathy Hemoglobin F Azacitidine Female Endothelium Vascular Laminin business Thrombospondins Biomarkers medicine.drug |
| Zdroj: | Blood. 102(12) |
| ISSN: | 0006-4971 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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