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For the past half century, thiopurines have earned themselves a reputation as effective anti-cancer and immunosuppressive drugs. Thiopurine S-methyltransferase (TPMT) is involved in the metabolism of all thiopurines and is one of the main enzymes that inactivates mercaptopurine. 6-MP is now used as a combination therapies for maintenance therapy of children with acute lymphocytic leukemia (ALL). In all patients receiving mercaptopurine, there is a risk of bone marrow suppression. TPMT activity is inherited as a monogenic, co-dominant trait. More than 25 variants are known. Genetic testing is available for several TPMT variant alleles. Most commonly TPMT*2, *3A, and *3C are tested for, which account for >90% of inactivating alleles. Differences in DNA that alter the expression or function of proteins that are targeted by drugs can contribute significantly to variation in the responses of individuals.Genotyping may become part of routine investigations to help clinicians tailor drug treatment effectively. This success is mainly due to the development of combination therapies and stratification of patients according to risk of treatment failure and relapse, rather than the discovery of new drugs. The aim of this study was to investigate the effect of genotype or methyltransferase enzyme activity before starting therapy in children with ALL. This can prevent the side effect of thiopurine drugs. In fact, the common polymorphism of this enzyme in population could be a prognostic factor in relation to drug use and treatment of patients with ALL.
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INTRODUCTION: Arsenic trioxide is effective and approved for treatment of relapsed or refractory acute promyelocytic leukemia (APL) cases resistant to all-trans retinoic acid (ATRA), but its effect on new cases of APL is not clear. MATERIALS AND METHODS: We studied 111 patients with APL. Arsenic trioxide was infused at 0.15 mg/kg daily dose, until complete remission was achieved. Then, after 28 days of rest, arsenic trioxide was infused daily for 28 days as consolidation therapy. We studied minimal residual disease (MRD) by semi-sensitive reverse transcription polymerase chain reaction (RT-PCR) on peripheral blood samples. RESULTS: Complete remission was observed in 95 patients (85.6%). With the median (range) follow-up period of 16.5 (1-57) months, 1- and 2-year disease-free survival was 88.3% and 63.7%, respectively; 24 patients relapsed, 19 of whom achieved a second complete remission, again by arsenic trioxide. Third and fourth remissions were seen in some relapsed patients, again by arsenic trioxide. For patients in complete remission, 1- and 3-year survival was 95.5% and 87.6%, respectively. MRD was positive in four (8.3%) out of 48 cases during 1 year after remission induction; three of them relapsed clinically. CONCLUSIONS: Arsenic trioxide is effective as first-line treatment for APL. Results of arsenic trioxide combination therapy with chemotherapy/ATRA requires further study.
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Antineoplásicos/uso terapéutico , Arsenicales/uso terapéutico , Leucemia Promielocítica Aguda/tratamiento farmacológico , Óxidos/uso terapéutico , Adolescente , Adulto , Anciano , Trióxido de Arsénico , Niño , Supervivencia sin Enfermedad , Femenino , Humanos , Leucocitosis , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neoplasia Residual/tratamiento farmacológico , Proteínas de Fusión Oncogénica/genética , Proteínas de Fusión Oncogénica/metabolismo , Pronóstico , Inducción de Remisión , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
Conflicting results have been published on the frequency of clonal patterns of X-chromosome inactivation in female patients with aplastic anaemia. Previous studies have used DNA methylation to measure X-inactivation, but aberrant methylation is known to occur in some situations. We have developed a non-radioactive reverse transcription polymerase chain reaction (RT-PCR) method to study expression of the polymorphism at nt. 1311 of the G6PD gene at the RNA level. Using this, and a similar method for the iduronate-2-sulfatase (IDS) gene, we have re-evaluated X-inactivation in AA patients. 32/35 normal individuals showed polyclonal haemopoiesis. Patients with presumed clonal diseases showed both monoclonal and polyclonal patterns, consistent with previous reports. Overall, clonal patterns were observed in granulocytes of 10/26 AA patients (38%), a significantly higher proportion than in controls (p<0.01). Two cases showed discordance between lymphocytes and granulocytes, indicating clonality arising within the myeloid lineage. Eight cases showed clonal patterns in both myeloid and lymphoid cells, indicating the involvement of a pluripotent stem cell. Clonal patterns did not correlate with age, but there appeared to be an association with duration of disease. In PNH patients, CD59-negative cells showed clonal patterns of X-inactivation. In two cases, however, clonal patterns were also detected in CD59-positive cells.
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Anemia Aplásica/genética , Células Clonales , Compensación de Dosificación (Genética) , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Alelos , Anemia Aplásica/patología , Femenino , Expresión Génica , Genotipo , Glucosafosfato Deshidrogenasa/genética , Hematopoyesis , Hemoglobinuria Paroxística/genética , Humanos , Iduronato Sulfatasa/genética , Polimorfismo GenéticoRESUMEN
Long-term survivors of aplastic anemia (AA) have a high incidence of clonal disorders, in particular paroxysmal nocturnal hemoglobinuria (PNH), myelodysplastic syndromes (MDS), and acute nonlymphocytic leukemia. To investigate the potential involvement of N-RAS gene mutations in the predisposition to leukemic evolution, a subset of patients at potentially increased risk for clonal disease was selected based on evidence of existing clonal evolution. Nine patients showed a monoclonal pattern of X-chromosome inactivation, 18 demonstrated a PNH clone, and in 3 MDS developed during the course of this study. No mutations were detected during the aplastic phase of disease; 2 of 3 patients with MDS after AA also showed no mutations. However, in 1 patient in whom the disease transformed from AA/PNH to MDS, a mutation of GGT --> GAT at N-RAS codon 13 became detectable, whereas the PNH mutation disappeared. The authors conclude that N-RAS mutations are not an early event preceding transformation of AA or AA/PNH to leukemia. In a subset of patients, RAS mutations may occur at the time of evolution to MDS, but preexisting RAS mutations do not explain the propensity of AA to leukemogenesis. Although PNH is also associated with leukemia, this may arise in the non-PNH cells, indicating that PIG-A gene mutation is not per se oncogenic. (Blood. 2000;95:646-650)
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Anemia Aplásica/genética , Genes ras , Hemoglobinuria Paroxística/genética , Leucemia Mieloide Aguda/genética , Síndromes Mielodisplásicos/genética , Eliminación de Secuencia , Adulto , Anciano , Secuencia de Aminoácidos , Anemia Aplásica/sangre , Anemia Aplásica/complicaciones , Anemia Aplásica/fisiopatología , Antígenos CD/análisis , Secuencia de Bases , Progresión de la Enfermedad , Eritrocitos/inmunología , Exones , Femenino , Eliminación de Gen , Predisposición Genética a la Enfermedad , Glicosilfosfatidilinositoles/metabolismo , Hemoglobinuria Paroxística/sangre , Hemoglobinuria Paroxística/complicaciones , Hemoglobinuria Paroxística/fisiopatología , Humanos , Leucocitos/inmunología , Masculino , Proteínas de la Membrana/genética , Persona de Mediana Edad , Datos de Secuencia Molecular , Polimorfismo Conformacional Retorcido-Simple , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Cromosoma XRESUMEN
Paroxysmal nocturnal haemoglobinuria (PNH) is an acquired stem cell abnormality which frequently develops in patients with aplastic anaemia. The disease is due to somatic mutations in the PIG-A gene, and a variety of mutations have been reported. The majority are point mutations, or small insertions and deletions resulting in a frameshift. Previous insertions reported have all been within the range of 1-10 bp. We describe here a patient with PNH due to a large insertion of 88 bp; DNA sequencing showed this to be a tandem repeat of PIG-A sequences. The same mutation could be found in granulocytes and lymphocytes, indicating a pluripotent stem cell origin.
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Elementos Transponibles de ADN/genética , Hemoglobinuria Paroxística/genética , Proteínas de la Membrana/genética , Secuencia de Bases , Exones/genética , Femenino , Glicosilfosfatidilinositoles/genética , Humanos , Persona de Mediana Edad , Datos de Secuencia Molecular , Mutación/genética , Reacción en Cadena de la PolimerasaRESUMEN
X chromosome inactivation is widely studied using DNA sequence polymorphisms and DNA methylation as a surrogate measure of inactivation, but the correlation of methylation with inactivation is not perfect. Thus, it may be better to study sequence polymorphisms expressed in the mRNA. A recent paper reported use of a silent C/T polymorphism at nt 1311 of the G6PD cDNA, and this polymorphism was reported to have a frequency of 40% in all ethnic groups. We have screened 218 English and 50 Iranian subjects by PCR and restriction digestion; 53/218 (24%) British and 22/50 (44%) Iranian subjects were heterozygous. Thus, X inactivation studies using this polymorphism may be useful in some populations, including Iran, but much less so in the UK.