Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.1.1.67 (thiopurine methyltransferase)
551 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

6-mercaptopurine (6-MP) can be inactivated by S-methylation, which is catalysed by thiopurine methyltransferase (TPMT). An alternative metabolic route leads to the formation of cytotoxic 6-thioguanine nucleotides (6-TGN). To investigate whether these two pathways compete with each other to affect the therapeutic response to 6-MP, 6-TGN concentrations and TPMT enzymatic activity were measured in erythrocytes (RBC) from 95 children on long-term 6-MP therapy for lymphoblastic leukaemia (ALL). RBC TPMT activities were also measured in 130 control children and 104 long-term survivors of ALL no longer on treatment. The 95 children on 6-MP showed wide interindividual differences in RBC 6-TGN concentrations at the full protocol dose of 75 mg/m2, and RBC 6-TGN concentrations correlated negatively with RBC TPMT activity. Children with 6-TGN concentrations below the group median had higher TPMT activities and a higher subsequent relapse rate. 50 of the 104 long-term survivors had been treated with "gentle" low-dose protocols, and this subgroup contained an excess of children with lower TPMT activities compared with normal controls. These results indicate that genetically determined TPMT activity may be a substantial regulator of the cytotoxic effect of 6-MP, an effect which in turn could be important in influencing the outcome of therapy for childhood ALL.
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PMID:Genetic variation in response to 6-mercaptopurine for childhood acute lymphoblastic leukaemia. 197 80

The cytotoxic activity of 6-mercaptopurine (6-MP) is affected by thiopurine methyltransferase (TPMT), a genetically regulated and variable intracellular enzyme. 6-Thioguanine (6-TG), a closely related thiopurine, is less affected by that enzyme and so it may be a more reliable drug-at least for patients with constitutionally high TPMT activity. We attempted to assess its suitability as an alternative by comparing the pharmacokinetics of both drugs in a small group of children with lymphoblastic leukaemia (ALL). Patients were included who were in their second or subsequent remission, who would otherwise have received 6-MP, and on whom pharmacokinetic data concerning 6-MP metabolism had been collected in a previous remission. Plasma 6-TG concentrations were assayed following an oral dose of 40 mg m-2, and the accumulation and fluctuation of intracellular (erythrocyte, RBC) 6-TG nucleotides (6-TGNs) were measured at regular intervals during daily oral therapy. Seven children were studied. Plasma 6-TG concentrations were low and cleared within 6 h of oral dosing. At 7 days, 6-TGN concentrations ranged from 959 to 2361 pmol 8 x 10(-8) RBCs, in all cases significantly higher (P = 0.002) than those produced by the same patients on 6-MP. After a total therapy time of 35 patient months, a modest rise of alanine aminotransferase was seen on one occasion, otherwise no toxicity apart from myelosuppression was encountered. In the context used, 6-TG appears well tolerated and produces higher concentrations of intracellular cytotoxic metabolites than 6-MP. For children constitutionally 'resistant' to the traditional drug, if not all, it may be a preferable alternative.
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PMID:Is 6-thioguanine more appropriate than 6-mercaptopurine for children with acute lymphoblastic leukaemia? 831 12

Daily 6-mercaptopurine (6MP) forms the backbone of continuing chemotherapy for childhood lymphoblastic leukaemia (ALL). A major metabolic route is catalysed by thiopurine methyltransferase (TPMT). TPMT deficiency occurs in 1 in 300 individuals and results in high concentrations of thioguanine nucleotides (TGNs), cytotoxic 6MP metabolites. A leukaemic child taking 6MP repeatedly developed profound pancytopenias. TPMT deficiency was confirmed. TGN formation was then studied on attenuated 6MP dosages. Four weekly oral doses of 75 mg/m2 6MP produced TGNs of 2348 pmol/8 x 10(8) red cells, nearly double the maximum TGNs recorded in ALL children with TPMT activity taking long term daily 75 mg/m2 6MP. Grossly elevated TGN concentrations were also produced at 10% standard 6MP dosage (7.5 mg/m2 daily), accompanied by unacceptable 6MP toxicity (neutropenia, diarrhoea, vomiting). The child was eventually stabilised on 10% alternate day therapy and after 15 weeks TGNs were 1670 pmol, just above the upper end of the TGN range for ALL children with TPMT activity.
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PMID:Thiopurine methyltransferase deficiency in childhood lymphoblastic leukaemia: 6-mercaptopurine dosage strategies. 925 29

Advances in the molecular and immunologic characterization of leukemic cells have greatly aided the diagnosis and risk assignment of ALL, as well as the monitoring of bone marrow samples for minimal residual disease. Currently, 75% of childhood cases have biologically and therapeutically relevant genetic abnormalities. Although gene discoveries in ALL have not been directly translated into effective therapy, there is every reason to believe that this disease will eventually yield to molecular intervention. In the meantime, efforts are being made to enhance the efficacy of existing regimens while reducing their toxic side effects. We have learned, for example, the following: high-dose methotrexate is more effective than lower-dose methotrexate, especially for T-cell ALL; patients who need drastic adjustment of mercaptopurine dosage due to thiopurine S-methyltransferase deficiency can be prospectively identified; dexrazoxane (ICRF-187) could reduce anthracycline cardiotoxicity; granulocyte colony-stimulating factor can shorten hospital stays for febrile neutropenia after intensive remission induction therapy; and prolonged low-dose epipodophyllotoxin treatment may reduce the risk of therapy-induced acute myeloid leukemia without compromising treatment efficacy. The challenge now is to identify specific treatments for genetically defined subtypes of ALL.
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PMID:Acute lymphoblastic leukemia. 928 87

6-mercaptopurine, a key drug for the treatment of acute lymphoblastic leukaemia in children, is a prodrug metabolized into 6-thioguanine (6-TGN) which are the active compounds and into methylated metabolites, primary by thiopurine S-methyltransferase enzyme (TPMT). This enzyme displays important inter subject variability linked to a genetic polymorphism: when treated with standard doses of thiopurine, TPMT-deficient and heterozygous patients are at great risk for developing severe and potentially life-threatening toxicity (hematopoietic, hepatic, mucositis...) but show a better survival rate while patients with high TPMT activity (wild type) present lower peripheral red blood cells 6-TGN concentrations and a higher risk of leukemia relapse. Genotyping remains crucial before 6-MP administration at diagnosis to identify patients with homozygous mutant TPMT genotype and therefore prevent severe and life-threatening toxicity, and to individualize therapy according to TMPT genotype. Follow-up of ALL treatment should preferentially be based on repeated determinations of intracellular active metabolites (6-thioguanine nucleotides) and methylated metabolites in addition to haematological surveillance.
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PMID:[Therapeutic drug monitoring of 6-thioguanine nucleotides in paediatric acute lymphoblastic leukaemia: interest and limits]. 2069 69

Of 1614 Nordic children with ALL that were treated according to the NOPHO ALL92 protocol, 20 developed an SMN (cumulative risk at 12 years: 1.6%). Sixteen of the twenty SMNs were acute myeloid leukemias or myelodysplasias, and 9 of these had either monosomy 7 (n=7) or 7q deletions (n=2). In Cox multivariate analysis longer duration of oral MTX/6MP maintenance therapy (p=0.02; being longest for standard risk patients) and presence of high-hyperdiploidy (p=0.07) were related to an increased risk of SMN. In 524 patients we determined the erythrocyte activity of thiopurine methyltransferase (TPMT), which methylates 6MP and its metabolites, and thus reduces cellular levels of cytotoxic 6-thioguanine nucleotides. The TPMT activity was significantly lower in those that did compared to those that did not develop an SMN (Median: 12.1 vs 18.1 IU/ml; p=0.02). Among 427 TPMT wild type patients, those who developed SMN received higher 6MP doses than the remaining (69.7 vs 60.4 mg/m(2), p=0.03), which may reflect increased levels of methylated metabolites that inhibit purine de novo synthesis and thus enhance incorporation of 6-thioguanine nucleotides into DNA. In conclusion, the duration and intensity of 6MP/MTX maintenance therapy of childhood ALL may influence the risk of SMN.
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PMID:Epidemiology of therapy-related myeloid neoplasms after treatment for pediatric acute lymphoblastic leukemia in the nordic countries. 2171 78

Methotrexate/6-mercaptopurine maintenance therapy of childhood acute lymphoblastic leukemia is challenged by treatment-related hepatotoxicity, failure to achieve the myelosuppressive target, and lack of direct parameters for monitoring treatment efficacy or even intensity. Patients with low thiopurine methyltransferase (TPMT) activity have lower levels of hepatotoxic methylated thiopurine metabolites (MeMPs), higher levels of thioguanine nucleotides (TGNs), and reduced relapse rates. Addition of 6-thioguanine to maintenance therapy of a child with ALL and high TPMT activity increased the TGN/MeMP index in erythrocytes 5.5-fold, mimicking the more favorable thiopurine metabolism seen in patients with low TPMT activity.
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PMID:Pharmacokinetics of 6-Thioguanine and 6-Mercaptopurine Combination Maintenance Therapy of Childhood ALL: Hypothesis and Case Report. 2517 55

6-mercaptopurine, a key drug for the treatment of acute lymphoblastic leukaemia in children, is a prodrug metabolized into 6-thioguanine (6-TGN) which are the active compounds and into methylated metabolites, primary by thiopurine S-methyltransferase enzyme (TPMT). This enzyme displays important inter subject variability linked to a genetic polymorphism: when treated with standard doses of thiopurine, TPMT-deficient and heterozygous patients are at great risk for developing severe and potentially life-threatening toxicity (hematopoietic, hepatic, mucositis. . . ) but show a better survival rate while patients with high TPMT activity (wild type) present lower peripheral red blood cells 6-TGN concentrations and a higher risk of leukemia relapse. Genotyping remains crucial before 6-MP administration at diagnosis to identify patients with homozygous mutant TPMT genotype and therefore prevent severe and life-threatening toxicity, and to individualize therapy according to TMPT genotype. Follow-up of ALL treatment should preferentially be based on repeated determinations of intracellular active metabolites (6-thioguanine nucleotides) and methylated metabolites in addition to haematological surveillance.
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PMID:[Not Available]. 2739 85

Hepatotoxicity is a known toxicity to treatment of childhood acute lymphoblastic leukemia. Hepatotoxicity occurs during maintenance therapy and is caused by metabolites of 6-Mercaptopurine (6 MP) and Methotrexate (MTX). Our objective was to investigate the association between alanine aminotransferases (ALAT) levels and relapse rate. We included 385 patients enrolled in the NOPHO ALL-92 protocol. Data on ALAT levels, 6 MP and MTX doses, cytotoxic MTX/6 MP metabolites, and thiopurine methyltransferase (TPMT) activity were prospectively registered. In total, 91% of the patients had a mean ALAT (mALAT) level above upper normal limit (40 IU/L) and ALAT levels were positively correlated to 6 MP doses (rs=0.31; P<0.001). In total, 47 patients suffered a relapse, no difference in mALAT levels were found in these compared with nonrelapse patients (median, 107 vs. 98 IU/L; P=0.39). mALAT levels in patients classified as TPMT high activity (TPMT) were higher than in TPMT low-activity patients (median, 103 vs. 82 IU/L; P=0.03). In a Cox regression model risk of relapse was not associated with ALAT levels (P=0.56). ALAT levels increased 2.7%/month during the last year of maintenance therapy (P<0.001). In conclusion, elevated ALAT levels are associated with TPMT and may indicate treatment adherence in these patients. If liver function is normal, elevated ALAT levels should not indicate treatment adaptation.
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PMID:Hepatotoxicity During Maintenance Therapy and Prognosis in Children With Acute Lymphoblastic Leukemia. 2806 Jan 15

Despite more than 80% long term survival in ALL, morbidity due to drug related myelotoxicity remains high. Germline variants of thiopurine metabolizing enzymes (TPMT and ITPA) have been described which are associated with increased drug toxicity during maintenance phase, but their prevalence in different ethnic groups is variable to account for relatively high myelotoxicity incidence. NUDT15 variant (rs116855232) has been recently identified as a novel polymorphism related with thiopurine-induced leucopenia in inflammatory bowel disease and ALL. Current review highlights the scientific data on NUDT15 enzyme variant and its relation to 6-MP toxicity in various ethnic populations.
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PMID:Emerging role of NUDT15 polymorphisms in 6-mercaptopurine metabolism and dose related toxicity in acute lymphoblastic leukaemia. 2896 8


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