title: 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.affiliation: University of Illinois at Chicago, Section of Hem/Onc, MBRB Rm 3150 (MC734), 900 S Ashland Ave, Chicago, IL 60607, USA. yogen@uic.edu
authors.forename: Yogen
authors.initials: Y
authors.lastname: Saunthararajah
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Hillery
authors.forename: Don
authors.initials: D
authors.lastname: Lavelle
authors.forename: Robert
authors.initials: R
authors.lastname: Molokie
authors.forename: Louise
authors.initials: L
authors.lastname: Dorn
authors.forename: Linda
authors.initials: L
authors.lastname: Bressler
authors.forename: Stefana
authors.initials: S
authors.lastname: Gavazova
authors.forename: Yi-Hsiang
authors.initials: YH
authors.lastname: Chen
authors.forename: Ronald
authors.initials: R
authors.lastname: Hoffman
authors.forename: Joseph
authors.initials: J
authors.lastname: DeSimone
mesh_terms: D000328:Adult; D000755:Anemia, Sickle Cell / Q000097:blood / Q000150:complications / Q000188:drug therapy*; D001374:Azacitidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*; D015415:Biomarkers / Q000032:analysis; D001777:Blood Coagulation / Q000187:drug effects; D001853:Bone Marrow / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D019175:DNA Methylation / Q000187:drug effects; D000077209:Decitabine; D004730:Endothelium, Vascular / Q000473:pathology; D004912:Erythrocytes / Q000187:drug effects* / Q000473:pathology; D005260:Female; D005319:Fetal Hemoglobin / Q000032:analysis* / Q000187:drug effects; D006410:Hematopoiesis / Q000187:drug effects*; D006801:Humans; D007249:Inflammation; D007797:Laminin / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D019699:Thrombospondins / Q000378:metabolism; D014652:Vascular Diseases / Q000209:etiology / Q000517:prevention & control
chemical_list: D015415:Biomarkers; D007797:Laminin; D019699:Thrombospondins; D000077209:Decitabine; D005319:Fetal Hemoglobin; D001374:Azacitidine