5-Azacytidine acts directly on both erythroid precursors and progenitors to increase production of fetal hemoglobin.
The effect of 5-azacytidine on erythroid precursors and progenitors was studied in nine patients with sickle cell anemia or severe thalassemia. Each patient received the drug intravenously for 5 or 7 d. 5-Azacytidine caused a four- to sixfold increase in gamma-messenger RNA concentration in bone marrow cells of eight of the nine patients and decreased the methylation frequency of a specific cytosine residue in the gamma-globin gene promoter in all nine patients. Within 2 d of the start of drug treatment there was a rise in the percentage of reticulocytes containing fetal hemoglobin (HbF; F-reticulocytes) without a significant change in the total number of reticulocytes, which suggested that there was a direct action of 5-azacytidine on erythroid precursors. Late erythroid progenitors (CFU-E), present in bone marrow after 2 d of drug administration, formed colonies containing an increased amount of HbF as compared with control colonies. Moreover, the number of CFU-E derived colonies was not decreased at these early times, which suggested that there was a direct action of 5-azacytidine on erythroid progenitors in the absence of cytotoxicity. Exposure of normal bone marrow cells in tissue culture to 5-azacytidine for 24 h reproduced both of these effects as judged during subsequent colony formation. The combined direct effects of 5-azacytidine on both the erythroid precursor and progenitor compartments resulted in an increase in HbF synthesis that was sustained for 2-3 wk. Toxicity to bone marrow as reflected by cytoreduction was evident after treatment in some patients but was not accompanied by an increase in HbF production. A correlation was found between the effects of 5-azacytidine on bone marrow, as assessed by in vitro measurements, and the hematological response of the individual patients to drug treatment.
Humphries
R K
RK
Dover
G
G
Young
N S
NS
Moore
J G
JG
Charache
S
S
Ley
T
T
Nienhuis
A W
AW
D000328:Adult; D000755:Anemia, Sickle Cell / Q000097:blood / Q000188:drug therapy; D001374:Azacitidine / Q000494:pharmacology*; D004912:Erythrocytes / Q000187:drug effects* / Q000378:metabolism; D004920:Erythropoiesis / Q000187:drug effects; D005319:Fetal Hemoglobin / Q000096:biosynthesis*; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008875:Middle Aged; D012333:RNA, Messenger / Q000378:metabolism; D013789:Thalassemia / Q000097:blood / Q000188:drug therapy
D012333:RNA, Messenger; D005319:Fetal Hemoglobin; D001374:Azacitidine