5-azacytidine selectively increases gamma-globin synthesis in a patient with beta+ thalassemia.
5-Azacytidine is a cytidine analogue that is capable of activating repressed genes in tissue-culture cells and has been shown to increase hemoglobin-F production in anemic baboons. This drug was administered to a patient with severe beta-thalassemia in an attempt to stimulate hemoglobin-F production. After seven days of 5-azacytidine treatment, gamma-globin synthesis increased approximately sevenfold, temporarily normalizing the patient's unbalanced globin synthesis. Erythropoiesis became more effective, leading to a temporary increase in the absolute reticulocyte count (from 5000 to 22,000 per cubic millimeter) and in hemoglobin concentration (from 8.0 to 10.8 g per deciliter). Hypomethylation of bone-marrow DNA near both the gamma-globin and epsilon-globin genes was directly demonstrated. At the time of peak drug effect, about 7000 gamma-globin messenger RNA molecules were present per erythroid bone-marrow cell, in contrast to 10 to 15 epsilon-globin messenger RNA molecules per cell. 5-Azacytidine selectivity increases gamma-globin synthesis and therefore provides a new approach to the treatment of severe beta-thalassemia. Further studies will be required to evaluate the efficacy, risks, and long-term toxicity of 5-azacytidine (or related compounds) before this approach can be used as a therapy for patients with disorders of hemoglobin synthesis.
D000328:Adult; D001374:Azacitidine / Q000494:pharmacology* / Q000627:therapeutic use; D004247:DNA / Q000378:metabolism; D004920:Erythropoiesis / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D005914:Globins / Q000096:biosynthesis* / Q000235:genetics; D006454:Hemoglobins / Q000032:analysis; D006801:Humans; D008297:Male; D008745:Methylation; D012333:RNA, Messenger / Q000378:metabolism; D013268:Stimulation, Chemical; D013789:Thalassemia / Q000188:drug therapy / Q000378:metabolism*
D006454:Hemoglobins; D012333:RNA, Messenger; D005914:Globins; D004247:DNA; D001374:Azacitidine