Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0039730 (thalassemia)
 10,305 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

5-Azacytidine, a drug used in the treatment of acute leukaemias and beta-thalassemia, was administered i.p. to BALB/c mice at a dose of 2.0 mg/kg body wt. once a week for 50 weeks to test its carcinogenicity. The treatment induced a significant increase in lung tumours (males P less than 0.001, females P less than 0.05), lymphomas (males P less than 0.01, females P less than 0.01), skin tumours (males P less than 0.05, females P less than 0.01) in both sexes and mammary carcinomas (P less than 0.01) and a variety of other tumours in female mice. These results, with other investigations reported in literature, suggest that 5-azacytidine is carcinogenic in mice.
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PMID:5-Azacytidine carcinogenesis in BALB/c mice. 244 31

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.
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PMID:5-Azacytidine acts directly on both erythroid precursors and progenitors to increase production of fetal hemoglobin. 257

5-Azacytidine transiently augments fetal hemoglobin production in patients with beta-thalassemia or sickle cell anemia. This change would probably be beneficial to such patients (e.g. a normal fetal gene product is substituted for a deficient or defective adult gene product) if HbF production could be sustained at high levels for prolonged periods. Even though the clinical use of 5-azacytidine is limited because of its presumed potential to cause cancer, studies with this drug have provided new insights into globin gene regulation and have stimulated the development of other strategies to increase HbF synthesis.
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PMID:Induction of hemoglobin F synthesis in patients with beta thalassemia. 258

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.
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PMID:5-azacytidine selectively increases gamma-globin synthesis in a patient with beta+ thalassemia. 618 86

We previously demonstrated that 5-azacytidine can selectively increase gamma-globin synthesis in a patient with beta +-thalassemia, prompting us to treat two patients with sickle cell anemia and two additional patients with beta + thalassemia. 5-Azacytidine (2 mg/kg/day) was continuously infused for 7 days with no apparent clinical toxicity. The gamma/beta-globin biosynthetic ratio increased fourfold to sixfold in the bone marrow cells of each patient after treatment and remained elevated for 7-14 additional days. Hypomethylation of DNA near the gamma-globin genes in bone marrow cells was demonstrated 2 days after beginning the 5-azacytidine infusion. The peripheral blood fetal hemoglobin (HbF) level increased from 6.0% to 13.7% in one patient with sickle cell anemia and from 1.6% to 8.9% in the second. Stractan gradient analyses of peripheral blood from patients with sickle cell anemia revealed a marked decrease in the percentage of dense cells (cells that contain increased amounts of HbS polymer when deoxygenated) following treatment. These observations provide an impetus to investigate the effects of repeated courses of 5-azacytidine in a small group of severely ill patients to determine whether this drug may have a role in the treatment of patients with sickle cell anemia and beta-thalassemia.
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PMID:5-Azacytidine increases gamma-globin synthesis and reduces the proportion of dense cells in patients with sickle cell anemia. 619 99

5-Azacytidine, a cytidine analog, stimulated fetal hemoglobin synthesis in five patients who had either severe beta-thalassemia or sickle cell anemia. After treatment, a reduction in the frequency of methylated cytosine residues was observed at all Hpa II sites examined. Despite causing "global" hypomethylation, 5-azacytidine augmented the synthesis of gamma-globin only. Although gamma-gene hypomethylation and increased gamma-gene expression seem to be linked, hypomethylation near other genes was not sufficient to activate transcription. These data suggest that the gamma genes lie in a unique "preactivational" state responsive to hypomethylation, and that other genes are repressed in bone marrow cells by different mechanisms. DNA hypomethylation and an increased concentration of gamma-mRNA were observed in bone marrow cells 2 days after initiation of treatment, indicating that 5-azacytidine may act directly on differentiated erythroid precursors. This compound probably affects early erythroid progenitors as well, since an increased level of gamma-globin synthesis persists for 1-2 weeks after the drug is stopped. A direct effect on erythroid progenitors was also suggested by in vitro assays: Erythroid colonies derived from progenitor cells obtained on day 2 of treatment produced more Hb F than colonies derived from progenitors obtained before 5-azacytidine was given.
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PMID:DNA methylation and globin gene expression in patients treated with 5-azacytidine. 619 60