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43-449: The symptoms tend to be similar to AML in general with the following being possible symptoms: Easy bleeding from low platelets may include: Acute promyelocytic leukemia is characterized by a chromosomal translocation involving the retinoic acid receptor alpha ( RARA ) gene on chromosome 17 . In 95% of cases of APL, the RARA gene on chromosome 17 is involved in a reciprocal translocation with

86-455: A clinical remission in approximately 90% of patients with arsenic trioxide having a more favorable side effect profile. ATRA therapy is associated with the unique side effect of differentiation syndrome . This is associated with the development of dyspnea , fever, weight gain, peripheral edema and is treated with dexamethasone . The etiology of retinoic acid syndrome has been attributed to capillary leak syndrome from cytokine release from

129-458: A derivative of vitamin A , which plays an important role in cell growth, differentiation, and the formation of organs in embryonic development. Once retinoic acid binds to the RAR, the heterodimer initiates transcription and allows for its target genes to be expressed.   RA signaling has been correlated with several signaling pathways in early embryonic development . First, it participates in

172-407: A high temperature ( > 110 °C) cubic As 4 O 6 , containing molecular As 4 O 6 , and two related polymeric forms. The polymers, which both crystallize as monoclinic crystals, feature sheets of pyramidal AsO 3 units that share O atoms. Smelting and related ore processing often generate arsenic trioxide, which poses a risk to the environment . For example,

215-423: A hybrid protein with altered functions. This fusion protein binds with enhanced affinity to sites on the cell's DNA, blocking transcription and differentiation of granulocytes. It does so by enhancing interaction of nuclear co-repressor (NCOR) molecule and histone deacetylase (HDAC). Although the chromosomal translocation involving RARA is believed to be the initiating event, additional mutations are required for

258-543: A liquid form of arsenic trioxide that can be given by mouth. Organoarsenic compounds , such as feed additives ( roxarsone ) and medication ( neosalvarsan ), are derived from arsenic trioxide. Industrial uses include usage as a precursor to forestry products, in colorless glass production, and in electronics. Being the main compound of arsenic , the trioxide is the precursor to elemental arsenic, arsenic alloys, and arsenide semiconductors . Bulk arsenic-based compounds sodium arsenite and sodium cacodylate are derived from

301-450: A medical treatment can lead to skin cancer. Reproductive problems (high incidences of miscarriage, low birth weight, congenital deformations) have also been indicated in one study of women exposed to arsenic trioxide dust as employees or neighbours of a copper foundry. In the U.S., the OSHA 1910.1018 occupational permissible exposure limit for inorganic arsenic compounds in breathing zone air

344-438: A synthetic retinoid, tamibarotene , is licensed for use as a treatment for ATRA-resistant APL. Some evidence supports the potential therapeutic utility of histone deacetylase inhibitors such as valproic acid or vorinostat in treating APL. According to one study, a cinnamon extract has effect on the apoptotic process in acute myeloid leukemia HL-60 cells. Prognosis is generally good relative to other leukemias. Because of

387-401: A translocation of the long arms of chromosomes 15 and 17. On rare occasions, a cryptic translocation may occur which cannot be detected by cytogenetic testing ; on these occasions PCR testing is essential to confirm the diagnosis. APL is unique among leukemias due to its sensitivity to all- trans retinoic acid (ATRA; tretinoin), the acid form of vitamin A . Treatment with ATRA dissociates

430-430: A type of cancer known as acute promyelocytic leukemia . For this use it is given by injection into a vein . Common side effects include vomiting, diarrhea, swelling, shortness of breath, and headaches. Severe side effects may include APL differentiation syndrome and heart problems. Use during pregnancy or breastfeeding may harm the baby. Its mechanism in treating cancer is not entirely clear. Arsenic trioxide

473-582: Is 0.010 mg/m . Arsenic trioxide can be generated via routine processing of arsenic compounds including the oxidation (combustion) of arsenic and arsenic-containing minerals in air . Illustrative is the roasting of orpiment , a typical arsenic sulfide ore. Most arsenic oxide is, however, obtained as a volatile by-product of the processing of other ores. For example, arsenopyrite , a common impurity in gold- and copper-containing ores, liberates arsenic trioxide upon heating in air. The processing of such minerals has led to numerous cases of poisonings, and after

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516-516: Is a nuclear receptor that in humans is encoded by the RARA gene . NR1B1 is a gene with a protein product and has a chromosomal location of 17q21.2. RARA codes for the nuclear hormone receptor retinoic acid receptor, alpha subtype, a transcription factor . There are another two subtypes of RARs: beta and gamma subtypes. Retinoid signaling is transduced by two families of nuclear receptors, retinoic acid receptor ( RAR ) and retinoid X receptor ( RXR ), which form RXR/RAR heterodimers . In

559-729: Is an amphoteric oxide, and its aqueous solutions are weakly acidic . Thus, it dissolves readily in alkaline solutions to give arsenites . It is less soluble in acids, although it will dissolve in hydrochloric acid . With anhydrous HF and HCl, it gives AsF 3 and the trichloride: Only with strong oxidizing agents such as ozone , hydrogen peroxide , and nitric acid does it yield arsenic pentoxide , As 2 O 5 or its corresponding acid: In terms of its resistance to oxidation, arsenic trioxide differs from phosphorus trioxide , which readily combusts to phosphorus pentoxide . Reduction gives elemental arsenic or arsine ( AsH 3 ) depending on conditions: This reaction

602-436: Is capable of inducing remission but it is short-lived in the absence of concurrent "traditional" chemotherapy. As of 2013 the standard of treatment for concurrent chemotherapy has become arsenic trioxide , which combined with ATRA is referred to ATRA-ATO; before 2013 the standard of treatment was anthracycline (e.g. daunorubicin , doxorubicin , idarubicin or mitoxantrone )-based chemotherapy. Both chemotherapies result in

645-436: Is characterized by the presence of the t(15;17) translocation or PML/RAR-alpha gene expression; and for induction of remission and consolidation in patients with acute promyelocytic leukemia who are refractory to, or have relapsed from, retinoid and anthracycline chemotherapy, and whose acute promyelocytic leukemia is characterized by the presence of the t(15;17) translocation or PML/RAR-alpha gene expression. Arsenic trioxide

688-510: Is comparable to the rate seen in patients treated with ATRA and anthracycline-based therapy. It produces less cardiotoxicity than anthracycline-based treatments and hence may be preferable in these patients. According to recent updates, the combination of ATRA and arsenic trioxide (ATO) is now preferred for induction therapy in many cases, offering at least as effective results with fewer side effects compared to traditional chemotherapy. In cases of relapse, options include re-treatment with ATO or

731-422: Is controversial. Arsenic trioxide (As 2 O 3 ) is currently being evaluated for treatment of relapsed/refractory disease. Remission with arsenic trioxide has been reported. Studies have shown arsenic reorganizes nuclear bodies and degrades the mutant PML-RAR fusion protein. Arsenic also increases caspase activity which then induces apoptosis . It does reduce the relapse rate for high risk patients. In Japan

774-461: Is less expensive but is less available. It works by encouraging the proteosome breakdown of retinoic acid receptor alpha , by moving the protein on to the nuclear matrix and increasing ubiquitination . In the 1970s, Chinese researcher Zhang Tingdong and colleagues discovered this use. It was approved for leukemia treatment in the United States in 2000. University of Hong Kong developed

817-478: Is toxic to living organisms. Arsenic trioxide is readily absorbed by the digestive system. Ingestion of as little as 0.1 grams can be fatal. Chronic arsenic poisoning is known as arsenicosis. This disorder affects workers in smelters , in populations whose drinking water contains high levels of arsenic (0.3–0.4 ppm), and in patients treated for long periods with arsenic-based pharmaceuticals. Long-term ingestion of arsenic trioxide either in drinking water or as

860-459: Is used in the Marsh test . In the liquid and gas phase below 800 °C, arsenic trioxide has the formula As 4 O 6 and is isostructural with P 4 O 6 . Above 800 °C As 4 O 6 significantly dissociates into molecular As 2 O 3 , which adopts the same structure as N 2 O 3 . Three forms ( polymorphs ) are known in the solid state:

903-461: Is used to treat a type of cancer known as acute promyelocytic leukemia (APL). It may be used both in cases that are unresponsive to other agents, such as all-trans retinoic acid (ATRA) or as part of the initial treatment of newly diagnosed cases. This initial treatment may include combination therapy of arsenic trioxide with all-trans retinoic acid (ATRA). Effectiveness appears similar to Realgar/Indigo naturalis , which can be taken by mouth and

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946-518: The Giant Mine in Canada processed substantial amounts of arsenopyrite -contaminated gold ores. The poisonous properties of arsenic are the subject of an extensive literature. In Austria, there lived the so-called "arsenic eaters of Styria ", who ingested doses far beyond the lethal dose of arsenic trioxide without any apparent harm. Arsenic is thought to enable strenuous work at high altitudes, e.g. in

989-539: The RARA gene are a cardinal feature of acute promyelocytic leukemia (APL; MIM 612376). The most frequent translocation is t(15,17)(q21;q22), which fuses the RARA gene with the PML gene. RARA plays an important role in the establishment of the immune system by inducing T-regulatory cells , promoting tolerance, and controlling the differentiation of immature immune cells in the bone marrow called promyelocytes into mature white blood cells . The prevalence of this gene in

1032-491: The United States National Library of Medicine , which is in the public domain . Arsenic trioxide Arsenic trioxide is an inorganic compound with the formula As 2 O 3 . As an industrial chemical, its major uses include the manufacture of wood preservatives , pesticides , and glass . It is sold under the brand name Trisenox among others when used as a medication to treat

1075-912: The anthracyclines and etoposide ) due to the carcinogenic effects of these agents, with patients with breast cancer representing the majority of such patients. Around 40% of patients with APL also have a chromosomal abnormality such as trisomy 8 or isochromosome 17 which do not appear to impact on long-term outcomes. Retinoic acid receptor alpha 1DKF , 1DSZ , 3A9E , 3KMR , 3KMZ , 4DQM , 5K13 5914 19401 ENSG00000131759 ENSMUSG00000037992 P10276 Q6I9R7 P11416 NM_000964 NM_001024809 NM_001033603 NM_001145301 NM_001145302 NM_001176528 NM_001177302 NM_001177303 NM_009024 NM_001361954 NP_001138773.1 NP_001169999 NP_001170773 NP_001170774 NP_033050 NP_001348883 Retinoic acid receptor alpha ( RAR-α ), also known as NR1B1 (nuclear receptor subfamily 1, group B, member 1),

1118-922: The promyelocytic leukemia gene ( PML ) on chromosome 15 , a translocation denoted as t(15;17)(q22;q21). The RAR receptor is dependent on retinoic acid for regulation of transcription. Eight other rare gene rearrangements have been described in APL fusing RARA to promyelocytic leukemia zinc finger ( PLZF ), nucleophosmin , nuclear matrix associated, signal transducer and activator of transcription 5b ( STAT5B ), protein kinase A regulatory subunit 1α ( PRKAR1A ), factor interacting with PAPOLA and CPSF1 ( FIP1L1 ), BCL-6 corepressor or oligonucleotide / oligosaccharide -binding fold containing 2A ( NABP1 ) genes. Some of these rearrangements are ATRA-sensitive or have unknown sensitivity to ATRA because they are so rare; STAT5B/RARA and PLZF/RARA are known to be resistant to ATRA. The fusion of PML and RARA results in expression of

1161-526: The NCOR-HDAC complex from RAR and allows DNA transcription and differentiation of the immature leukemic promyelocytes into mature granulocytes by targeting the oncogenic transcription factor and its aberrant action. Unlike other chemotherapies, ATRA does not directly kill the malignant cells . ATRA induces the terminal differentiation of the leukemic promyelocytes, after which these differentiated malignant cells undergo spontaneous apoptosis on their own. ATRA alone

1204-564: The PML-RARα protein complex, in addition to chemotherapy and platelet transfusions . Retinoic acid receptor alpha has been shown to interact with: Knock-out mice studies showed that a deletion in one of the copies of the RARA gene did not create any observable defect, while deletion of both copies shows symptoms similar to that of vitamin A deficiency. This proved that all three subtypes of RARs work redundantly. This article incorporates text from

1247-414: The absence of ligand, DNA-bound RXR /RARA represses transcription by recruiting the corepressors NCOR1 , SMRT ( NCOR2 ), and histone deacetylase . When ligand binds to the complex, it induces a conformational change allowing the recruitment of coactivators , histone acetyltransferases , and the basic transcription machinery. Retinoic acid receptor-alpha, the protein, interacts with retinoic acid ,

1290-1184: The acuteness of onset compared to other leukemias, early death is comparatively more common. If untreated, it has median survival of less than a month. It has been transformed from a highly fatal disease to a highly curable one. The cause of early death is most commonly severe bleeding, often intracranial hemorrhage . Early death from hemorrhage occurs in 5–10% of patients in countries with adequate access to healthcare and 20–30% of patients in less developed countries. Risk factors for early death due to hemorrhage include delayed diagnosis, late treatment initiation, and high white blood cell count on admission. Despite advances in treatment, early death rates have remained relatively constant, as described by several groups including Scott McClellan, Bruno Medeiros, and Ash Alizadeh at Stanford University . Relapse rates are extremely low. Most deaths following remission are from other causes, such as second malignancies, which in one study occurred in 8% of patients. In this study, second malignancies accounted for 41% of deaths, and heart disease, 29%. Survival rates were 88% at 6.3 years and 82% at 7.9 years. In another study, 10-year survival rate

1333-507: The characteristic rearrangement. The presence of promyelocytes containing multiple Auer rods (termed faggot cells ) on the peripheral blood smear is highly suggestive of acute promyelocytic leukemia. Definitive diagnosis requires testing for the PML/RARA fusion gene. This may be done by polymerase chain reaction (PCR), fluorescence in situ hybridization , or conventional cytogenetics of peripheral blood or bone marrow. This mutation involves

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1376-508: The developing immune system leaves it subject to possible defects, the most common of which is a condition known as acute promyeloid leukemia (APL), caused by a somatic mutation described by the fusion of RARA and the PML gene located on chromosome 15 . This fusion results in the formation of the protein complex PML-RARα. Under normal circumstances, PML produces a tumor suppressing protein that works by inhibiting uncontrolled rapid cell growth. When

1419-442: The development of leukemia . RARA/PLZF gene fusion produces a subtype of APL that is unresponsive to tretinoin therapy and less responsive to standard anthracycline chemotherapy hence leading to poorer long-term outcomes in this subset of patients. Acute promyelocytic leukemia can be distinguished from other types of AML based on microscopic examination of the blood film or a bone marrow aspirate or biopsy as well as finding

1462-550: The differentiating promyelocytes. The monoclonal antibody , gemtuzumab ozogamicin , has been used successfully as a treatment for APL, although it has been withdrawn from the US market due to concerns regarding potential toxicity of the drug and it is not currently marketed in Australia, Canada or the UK. Given in conjunction with ATRA, it produces a response in around 84% of patients with APL, which

1505-481: The formation of the embryonic axis , which establishes symmetry in the offspring. RA also influences neural differentiation by regulating the expression of pro-neural induction factor Neurogenin 2 ( Neurog2 ). RA affects cardiogenesis , as it plays a role specifically in the formation of the atrial chambers of the heart. RA also plays a role in the development of the pancreas, kidneys, lungs, and extremities.   Translocations that always involve rearrangement of

1548-544: The mine is closed, the leftover trioxide waste will present environmental hazard (as was the case with the Giant Mine , for example). Only in China are arsenic ores intentionally mined. In the laboratory, it is prepared by hydrolysis of arsenic trichloride : As 2 O 3 occurs naturally as two minerals, arsenolite ( cubic ) and claudetite ( monoclinic ). Both are relatively rare secondary minerals found in oxidation zones of As-rich ore deposits. Arsenic trioxide

1591-440: The targeted drug gemtuzumab ozogamicin (Mylotarg). After stable remission was induced, the standard of care previously was to undergo 2 years of maintenance chemotherapy with methotrexate , mercaptopurine and ATRA. A significant portion of patients relapsed without consolidation therapy . In the 2000, European APL study, the 2-year relapse rate for those that did not receive consolidation chemotherapy (ATRA not included) therapy

1634-424: The trioxide. A variety of applications exploit arsenic's toxicity, including the use of the oxide as a wood preservative . Copper arsenates , which are derived from arsenic trioxide, are used on a large scale as a wood preservative in the U.S. and Malaysia, but such materials are banned in many parts of the world. This practice remains controversial. In combination with copper(II) acetate , arsenic trioxide gives

1677-418: The two proteins fuse together, their normal functions are hindered, resulting in the accumulation of promyelocytes in the bone marrow unable to differentiate past this immature phase. This fusion makes up for the cause of 98% of APL cases, with some other rare mutations and fusions making up the other 2%.6 Current treatment approaches include all-trans-retinoic acid (ATRA) which works by targeting and degrading

1720-564: The vibrant pigment known as Paris green used in paints and as a rodenticide. This application has been discontinued. Despite the well known toxicity of arsenic, arsenic trioxide was used in traditional Chinese medicine , where it is known as pi-shuang ( Chinese : 砒霜 ; pinyin : pīshuāng ; lit. 'arsenic frost'). In homeopathy , it is called arsenicum album . Some discredited patent medicines , e.g., Fowler's solution , contained derivatives of arsenic oxide. As with other inorganic arsenic compounds, arsenic trioxide

1763-460: Was 27% compared to 11% in those that did receive consolidation therapy (p<0.01). Likewise, in the 2000 US APL study, the survival rates in those receiving ATRA maintenance was 61% compared to just 36% without ATRA maintenance. However, recent research on consolidation therapy following ATRA-ATO, which became the standard treatment in 2013, has found that maintenance therapy in low-risk patients following this therapy may be unnecessary, although this

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1806-529: Was approved for medical use in the United States in 2000. It is on the World Health Organization's List of Essential Medicines . Approximately 50,000 tonnes are produced a year. Due to its toxicity, a number of countries have regulations around its manufacture and sale. Arsenic trioxide is indicated in combination with tretinoin for treatment of adults with newly-diagnosed low-risk acute promyelocytic leukemia whose acute promyelocytic leukemia

1849-536: Was estimated to be approximately 77%. Acute promyelocytic leukemia represents 10–12% of AML cases. The median age is approximately 30–40 years, which is considerably younger than the other subtypes of AML (70 years), however in elderly population APL has peculiar characteristics. Incidence is higher among individuals of Latin American or South European origin. It can also occur as a secondary malignancy in those that receive treatment with topoisomerase II inhibitors (such as

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