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.
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What are the chelating agents for beta thalassemia?
The most effective and engaging way for clinicians to learn, improve their practice, and prepare for board exams. ... Ritch PS, Anderson T. Evaluation of continuous infusion low …
How is thalassemia major diagnosed and treated?
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 …
What are the treatment strategies for beta-thalassemia?
· 5-azacytidine for beta thalassaemia? Ley TJ, Anagnou NP, Young NS, Nienhuis AW, DeSimone J, Heller P. PMID: 6186873 [PubMed - indexed for MEDLINE] Publication Types: ... Ethics, Medical; Fetal Hemoglobin/biosynthesis; Humans; Risk Assessment; Thalassemia/drug therapy* Therapeutic Human Experimentation; Substances. Fetal Hemoglobin;
What is the treatment for iron overload in thalassemia major?
· Lancet. 1983 Jan 1;1(8314-5):36-7. 5-azacytidine for beta-thalassaemia? [No authors listed] PMID: 6184580 [PubMed - indexed for MEDLINE] Publication Types: Editorial; MeSH Terms. Animals; ... Gene Expression Regulation/drug effects; Humans; Thalassemia/drug therapy* Substances. Fetal Hemoglobin;
How does fetal hemoglobin help beta thalassemia?
It has been generally assumed that reduction of the globin chain imbalance and resulting α globin excess by increasing expression of fetal or β globin, or by decreasing α globin, are all that is necessary to improve red cell survival and blood counts in β thalassemia.
How does thalassemia increase hemoglobin?
Many times people with thalassemia are prescribed a supplemental B vitamin, known as folic acid, to help treat anemia. Folic acid can help red blood cells develop. Treatment with folic acid is usually done in addition to other therapies.
How is beta thalassemia treated?
Treatment for beta thalassemia may include: Regular blood transfusions. Medications (to decrease amount of iron in the body, called chelation therapy) Surgical removal of the spleen (if necessary)
What is the best treatment for thalassemia?
Bone marrow and stem cell transplant from a compatible related donor is the only treatment that can cure thalassemia. It is the most effective treatment.
How long does it take for a 5-azaC to kill an animal?
The duration of 5-azaC treatment may vary from 10 to 15 days depending on the size of the tumor. The animals are killed when the tumors are reduced to 50 to 80% of the original size.
What is the name of the drug that converts a rat MSC to a multinucleated
Wakitani and his group were the first to show that a hypomethylating agent, 5-azacytidine, can convert rat MSC to multinucleated myotubes that contracted when exposed to acetylcholine and stained positively for skeletal muscle-specific myosin.59 Another landmark study by Makino et al. established a cardiomyocytic cell lineage after treating MSC with 5-azacytidine, expressing cardiomyocyte-specific genes, with evidence of ventricular-like action potentials 56 and expressing β -adrenergic and muscarinic receptors. 61 However, 5-azacytidine is known to be toxic in vivo.
Does 5-Aza inhibit DNA replication?
The dose and half-life of 5-Aza compounds modulate their demethylation function. For example, high doses of 5-Aza inhibit DNA replication and cell proliferation thereby cannot be incorporated into DNA but result in cytotoxicity [13].
What drugs alter the epigenome?
Other than methyl group donor nutrients, there are several other xenobiotics that have been shown to alter the epigenome. Drugs designed specifically to alter epigenetic marks for therapeutic purposes are slowly gaining ground (see Table 1). 5-Azacytidine (azacitidine) incorporates into DNA or RNA and irreversibly binds methyltransferase, and is a useful chemotherapeutic for myelodysplastic syndromes and has been in clinical trials for acute myeloid leukemia. A similar drug, 4-aza-2-deoxycytidine (decitabine), which incorporates into DNA only and inhibits methyltransferase, has been shown to extend the life span of patients with myelodysplastic syndromes from 15 to 24 months. Suberoylanilide hydroxamic acid (vorinostat) is a histone deacetylase inhibitor, which has been FDA approved to treat patients with cutaneous T-cell lymphoma. 2-Chloro-2′deoxyadenosine (cladribine), which was synthesized as a purine analog drug that inhibited adenosine deaminase and which has been used to treat hairy cell leukemia, has been shown to influence epigenetic marks, inhibiting S-adenosylhomocysteine hydrolase and subsequently DNA methylation. This may in part underlie the efficacy of this drug, which has recently shown promise for multiple sclerosis, hematologic malignancies, and autoimmune conditions.
Does vinclozolin increase DNA methylation?
Vinclozolin. Associated with transgenerational increases in DNA methylation. On the other hand, for many chemicals, there has been a link made between drug exposure and epigenetic change, but the precise mechanism underlying this change is poorly understood (see listing in Table 2 ).
How long does 5-azacytidine stay in remission?
Three patients stopped treatment after 5, 7, and 6 cycles: 1 because of digestive toxicity, 1 at his request, and 1 at the request of the physician. The first 2 patients remained in complete remission >18 months after discontinuing 5-azacytidine, whereas the last (PTCL4) relapsed 9 months after.
What are the recurrent mutations in TET2?
These 3 genes directly or indirectly regulate cytosine methylation and hydroxymethylation, and mutations of these genes result in changes in DNA methylation levels. 13 TET2, DNMT3A, and IDH1/2 are also mutated in myeloid neoplasms, especially acute myeloid leukemia and myelodysplastic syndromes. 13 Treatment with the hypomethylating agents (HMAs) 5-azacytidine and decitabine shows efficacy in these diseases, and the response rate to HMAs appears to correlate with TET2, IDH1/2, and/or DNMT3A mutations. 14-16 This suggests that HMAs could have activity against TFH-derived PTCL. We previously reported 2 patients with AITL and chronic myelomonocytic leukemia (CMML) who experienced sustained complete remission of both diseases after treatment with 5-azacytidine. 17, 18 Here, we expand these observations and describe the response and outcome of a retrospective series of 12 AITL patients who received 5-azacytidinefor concomitant myeloid neoplasm or used as compassionate therapy in relapsing/refractory AITL patients in the absence of available therapy or when such therapy was contraindicated, at the discretion of the physician.
What is a PTCL?
Peripheral T-cell lymphomas (PTCLs) are heterogeneous diseases resulting from the malignant transformation of mature T or natural killer cells. Their epidemiology varies widely, but PTCLs that derive from T follicular helper (TFH) cells, which include angioimmunoblastic T-cell lymphoma (AITL), follicular PTCL, and other nodal PTCLs with a TFH phenotype, 1 appear to be frequent among PTCLs. 2, 3 Patients have a poor prognosis, especially after relapse, with a median overall survival (OS) of ∼6 months. 4 The US Food and Drug Administration has approved pralatrexate, romidepsin, and belinostat for relapsing/refractory PTCL, but these 3 drugs still show limited activity in PTCL, with an overall response rate of ∼30%. 5-7 Thus, PTCL therapy is still an unmet medical need.
What is the pathology of thalassemia?
4 This pathology is characterized by decreased Hb production and red blood cell (RBC) survival, resulting from the excess of unaffected globin chain, which form unstable homotetramers that precipitate as inclusion bodies. α-Homotetramers in β-thalassemia are more unstable than β-homotetramers in α-thalassemia and therefore precipitate earlier in the RBC life span, causing marked RBC damage and severe hemolysis associated with ineffective erythropoiesis (IE) and extramedullary hemolysis. 5 ( Figure 1) In severe β-thalassemia, IE results in expanded marrow cavities that impinge on normal bone and cause distortion of the cranium, and of facial and long bones. In addition, erythroid activity proliferates in extramedullary hematopoietic sites, causing extensive lymphadenopathy, hepatosplenomegaly, and, in some cases, extramedullary tumors. 1
What is the diagnosis of -thalassemia minor?
β-thalassemia minor. In making a diagnosis of β-thalassemia minor, one must rule out the existence of iron deficiency, which may alter the usually elevated HbA 2 levels. High levels of HbF are also seen, depending on the underlying genetic mutation.
Is thalassemia a family history?
A diagnosis of α-thalassemia can be suspected based on factors, such as a family history of anemia and geographic and ethnic background, particularly if the patient comes from the Middle East, North Africa, and South east Asia, areas where α-thalassemia is common . The diagnosis is suspected in the presence of microcytic hypochromic anemia not because of iron deficiency, with normal HbA 2 levels in Hb electrophoresis identified. Silent carriers of α-thalassemia and/or α-thalassemia trait are in general clinically asymptomatic and may present with either normal blood count and morphology or with mild microcytic hypochromic anemia. A differential diagnosis must be made to distinguish patients with iron deficiency anemia from those with α-thalassemia trait. No specific treatment is recommended unless the patient is anemic. Folic acid (1-5 mg/day) can be given when the diet is deficient in folate and/or in the presence of infection, malabsorption, and where the patient is pregnant.
What is the reaction between LPI and LCI?
Both LPI and LCI react with reactive oxygen intermediate (ROI) producing noxious reactive oxygen species (ROS), for example, OH' radicals, which are highly reactive and oxidize DNA, proteins and lipid components of the cell. Deferiprone (DFP) chelates LCI alone or in combination with LPI by Deferiozamine (DFO).
Where is thalassemia most common?
Because thalassemia heterozygosity confers some immunity against malaria, there is a particularly high incidence of thalassemia (2.5%-25%) in the Mediterranean basin, the Middle East, the tropical and subtropical regions of Africa , the Asian subcontinent, and Southeast Asia, where milder forms of the disease are most commonly seen. Cases of thalassemia also occur sporadically in virtually every ethnic group and geographic location. 2, 3
When does hemoglobin HbA occur?
Consequently, newborn infants with severe β-globin chain abnormalities are asymptomatic until 4-6 months of age. Complete absence of α-globin chains results in intrauterine failure and hydropic births, whereas fetuses with the lack or dysfunction of 3 α-genes, which is known as hemoglobin H (HbH) disease, will survive gestation.
What is the classification of thalassemia?
The thalassemia syndrome is classified according to which of the globin chains, α or β, is affected. These 2 major groups, α- and β-thalassemia, are subclassified according to absent (α° and β°) or reduced (α + or β +) globin chain synthesis.