Effects of 5-aza-2'-deoxycytidine on fetal hemoglobin levels, red cell adhesion, and hematopoietic differentiation in patients with sickle cell disease.

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 gamma-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. gamma-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.

• Authors: Yogen Saunthararajah, Cheryl A Hillery, Don Lavelle, Robert Molokie, Louise Dorn, Linda Bressler, Stefana Gavazova, Yi-Hsiang Chen, Ronald Hoffman, Joseph DeSimone
• Journal: Blood (Blood) Vol. 102 Issue 12 Pg. 3865-70 (Dec 01 2003) ISSN: 0006-4971 [Print] United States
• PMID: 12907443 (Publication Type: Clinical Trial, Clinical Trial, Phase I, Clinical Trial, Phase II, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Biomarkers
• Laminin
• Thrombospondins
• Decitabine
• Fetal Hemoglobin
• Azacitidine

Topics

• Adult
• Anemia, Sickle Cell (blood, complications, drug therapy)
• Azacitidine (administration & dosage, analogs & derivatives, pharmacology)
• Biomarkers (analysis)
• Blood Coagulation (drug effects)
• Bone Marrow (pathology)
• Cell Adhesion (drug effects)
• Cell Differentiation (drug effects)
• DNA Methylation (drug effects)
• Decitabine
• Endothelium, Vascular (pathology)
• Erythrocytes (drug effects, pathology)
• Female
• Fetal Hemoglobin (analysis, drug effects)
• Hematopoiesis (drug effects)
• Humans
• Inflammation
• Laminin (metabolism)
• Male
• Middle Aged
• Thrombospondins (metabolism)
• Vascular Diseases (etiology, prevention & control)