Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.5.1.1 (asparaginase)
 2,695 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Twenty-six patients with newly diagnosed ALL (age range 15-49 years, median 32 years) received treatment comprising: cycles 1 and 2: adriamycin 30 mg/m2 days 1-3, vincristine: 2 mg days 1, 8, and 15, with prednisolone 40 mg daily, given until complete remission (CR). L-asparaginase 10000 units/m2, days 1-14, was given only with the first cycle. Cycle 3 consisted of 100 mg/m2 etoposide orally, days 1-5, and 1 gm/m2 bd cytosine arabinoside (ara-C) days 1-5. Cycles 1-3 were then repeated. Intrathecal methotrexate (MTX) 12.5 mg was given on day 1 of each treatment cycle. The first 12 consecutive patients received this chemotherapy alone, the subsequent 14 received, in addition, 3 micrograms/kg GM-CSF subcutaneously, from day 4 of cycles 1,2,4 and 5 (and from day 6 of cycles 3 and 6) until the absolute neutrophil count had reached 0.5 x 10(9)/1. All patients in whom CR was achieved then received prophylactic cranial irradiation. With the exception of those with T-ALL, this was followed by oral maintenance therapy consisting of 6-mercaptopurine, MTX, and cyclophosphamide for 3 years. Patients receiving GM-CSF did not have shorter intercycle times or a lower incidence of documented infections than those who did not receive it. The CR rate was 89% overall-uninfluenced by GM-CSF, but higher than that achieved previously at St Bartholomew's Hospital in an equivalent age-group.
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PMID:Intensive chemotherapy for adult acute lymphoblastic leukaemia given with or without granulocyte-macrophage colony stimulating factor. 900 54

The role of high-dose etoposide in the initial treatment of newly diagnosed adult ALL was assessed in a combined clinical and laboratory study. Therapy on protocol JH8802 consisted of two induction modules, module 1 containing prednisone, vincristine, high-dose etoposide and L-asparaginase (L-asp), followed by module 2 containing cytarabine (Ara-C) and daunorubicin (DNR). Patients achieving a complete remission (CR) underwent bone marrow transplantation (BMT) or intensive maintenance therapy. Results were compared to the preceding protocol (JH8302), which was similar except for omission of etoposide and L-asp. The CR rate following module 1 was 45% on protocol JH8802 and 9% on protocol JH8302 (p < 0.0002). Nonetheless, the two protocols had similar CR rates following module 2 (69% on protocol JH8302; 77% on JH8802) and indistinguishable survivals. Laboratory investigations performed on blasts harvested prior to chemotherapy revealed two factors that could potentially contribute to decreased etoposide sensitivity in ALL blasts. A flow microfluorimetry-based assay of nuclear DNR accumulation detected small P-glycoprotein (Pgp)-mediated decreases in drug accumulation in a quarter of the samples. Western blotting demonstrated that topoisomerase II was present in all samples but was diminished in amount compared to the Molt3 human ALL cell line. Immunoperoxidase staining with affinity-purified antibodies revealed that topo II alpha, the target for etoposide, was detectable in only a minority of the blasts (median 7.5%, range < 1-35%) at diagnosis. These observations raise the possibility that alterations in drug accumulation and diminished target enzyme levels might both limit the long-term efficacy of a single course of high dose etoposide administered early in the treatment of adult ALL.
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PMID:Addition of etoposide to initial therapy of adult acute lymphoblastic leukemia: a combined clinical and laboratory study. 902 88

We sought to determine the role of granulocyte colony-stimulating factor (G-CSF) as an adjunct therapy in high-dose cytarabine-containing chemotherapy (HD C/T) for children with acute leukemia. Seventeen patients, aged 9 months to 18 years old, 8 ALL and 9 AML, were treated with cytarabine (Ara-C) 1 g/m2 q12h for 8 doses with mitoxantrone, idarubicin, VP-16, or asparaginase. A total of 71 courses of HD C/T was given. G-CSF was not used in 14 courses (Group A). Prophylactic G-CSF was given in 57 courses (Group B) as 200 microg/m2/d SC started one day after the completion of HD C/T and continued until the neutrophil recovery was maintained. The incidences of sepsis per course in Group A and Group B were 35.7% (5/14) and 40.4% (23/57), respectively. While 2 patients in Group A died of sepsis or pneumonia, none in Group B died. The mortality and delay in chemotherapy were fewer in Group B (P = 0.037 and 0.0006, respectively, Fisher exact test). There was a shorter average number of days of neutrophil <500/cumm, antibiotic usage, fever, and hospital stay in Group B (11, 8, 5, 17 days in Group B vs. 21, 17, 10, 37 days in Group A; P = 0.0001, log-rank test; 0.0006, 0.0023, 0.0001, Wilcoxon rank sum test, respectively). The incidence of neutropenic fever was lower in Group B, but the difference did not reach statistical significance (P = 0.06, Fisher exact test). We conclude that G-CSF as an adjunct therapy in HD C/T is effective in reducing mortality, days of neutropenia, antibiotic usage, fever, hospital stay, and frequency of delay in chemotherapy. The efficacy of this treatment approach requires further testing in a randomized, controlled trial.
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PMID:High-dose cytarabine-containing chemotherapy with or without granulocyte colony-stimulating factor for children with acute leukemia. 959 Jan 44

The diagnosis of 'ALL with maturation' (ALLm) is proposed. One hundred and one patients with untreated ALL were entered into this study. The diagnosis of ALLm was made when more than 20% of all nucleated elements in the bone marrow showed maturation beyond prolymphocytes by light microscopic examination. The mature-appearing leukemic cells showed the same immunophenotype to remaining lymphoblasts. The number of ALLm cases was 19 (18.8%). The mean age at presentation of ALLm was 29 +/- 18, older than that of 18 +/- 16 of the remaining typical ALL (ALLt) (P = 0.015). Remission was induced with daunorubicin, vincristine, prednisone and L-asparaginase. Only two of 19 ALLm patients achieved CR after 4 weeks induction chemotherapy. In contrast, 57 of 82 (69.5%) ALLt patients achieved CR after the same induction chemotherapy. There was no significant difference in immunophenotype of ALLm compared with ALLt. Labeling index of DNA topoisomerase IIalpha (TopoLI) was studied by immunohistochemistry. Initial TopoLI of ALLm (221 +/- 147) was much lower than that of ALLt (609 +/- 262, P = 0.005). Furthermore, the remaining leukemic cells after chemotherapy were not labeled with anti-DNA topoisomerase IIalpha. The P53 protein was expressed in nine of 18 ALLm cases (50.0%) and P-glycoprotein was not expressed in ALLm cases. Twelve of 19 ALLm cases were studied for carrying bcr/abl fusion by karyotyping and/or fluorescent in situ hybridization. Only two cases revealed bcr/abl fusion. In conclusion, ALLm is a separate entity of ALL which has a very poor clinical course and is independent of other prognostic factors. The morphologically mature leukemic cells are in resting GO phase.
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PMID:Acute lymphoblastic leukemia with maturation--a new entity with clinical significance. 963 14

Venous thromboses (VT) in children with ALL who were treated according to the COALL-89 protocol were reported to occur with a frequency of 2.1% (6/286). 4/6 of the reported VT were catheter related. However, in other cohorts of ALL patients treated according to American protocols the incidence of severe thromboses was 2-11%. Most of the VT were not catheter related, but were atypical thromboses like sinus venous thromboses. In these patients hereditary thrombophilia risk factors seemed to play a major role. In a 6 year period including the COALL protocols -92 and -97 only 10/684 (1.5%) children presented with symptomatic VT, and 7/10 thromboses were catheter related. Every thrombotic event could be successfully treated either by heparin administration or fibrinolytic agents. 2/10 VT were secondary due to a septic event. 5 out of 8 primary VT occurred after asparaginase/dexamethasone application during the reinduction therapy. In conclusion, symptomatic thrombotic events are very rare in the COALL studies. Important risk factors for development of VT appeared to be central lines, asparaginase application and infectious/septic complications. However, the role of genetic risk factors of thrombosis in these patients has still to be determined.
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PMID:Low rate of severe venous thromboses in children with ALL treatment according to COALL-92 and -97 protocol. 1047 53

Asparaginase (ASP) is a standard component of the antileukemia armamentarium. There are currently 3 preparations of asparaginase available: (1) E. coli (ASP, Elspar); (2) the enzyme derived from Erwinia chrysanthemi (ERW, Erwinase); (3) pegaspargase (PEG, Oncaspar), the E. coli enzyme modified by covalent attachment of polyethylene glycol. This report describes the findings of 3 pharmacologic end points: ASP enzyme activity in patients' sera, depletion of asparagine and the development of anti-ASP antibodies. Pharmacokinetics and pharmacodynamic studies in a group of naive children with newly diagnosed ALL demonstrate a significant difference in apparent half-life (1.24 days E. coli vs. 0.65 ERW vs. 5.73 PEG; p < 0.001) and days of asparagine depletion (14-23 E. coli vs. 7-15 ERW vs. 26-34 PEG; p < 0.01) for the 3 different preparations. Data from Pediatric Oncology Group (POG) Protocol #8866 show that high antibody levels correlated with rapid ASP clearance and a significantly lower response rate (NR = 26% vs. CR + PR + 64%). The pharmacologic characteristics of ASP in terms of clearance of enzyme activity and ability to deplete serum asparagine was dependent upon the nature of the enzyme and are significantly altered in patients who develop anti-ASP antibodies regardless of their clinical status. In addition, these data demonstrate that ASP pharmacokinetics are directly related to its anti-leukemic effect. In order to maximize the therapeutic benefits of ASP, the optimal dose and schedule of treatment should be determined based on pharmacologic testing rather than by clinical criteria alone. Future studies will focus on the role of "silent hypersensitivity" as a mechanism of resistance to ASP and strategies to maximize the therapeutic efficacy of ASP as part of ALL therapy.
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PMID:The three asparaginases. Comparative pharmacology and optimal use in childhood leukemia. 1050 Aug 42

Coagulation disturbances are noticed, during ALL treatment with L-asparaginase, carrying risk of clotting complications. We examined 38 children with ALL (20 boys and 18 girls) aged 2-16 y., treated in 1996-1997 y. according to BFM and New York programmes. They received L-asparaginase of 10,000 and 25,000 U/m2 per dose at the beginning of induction therapy. The therapy started with E.coli L-asparaginase; in 16 cases the drug was changed to Erwinase. Decreasing of fibrinogen, antithrombin III concentration and prothrombin time was noticed. Infectious complications were established in 8 and clotting problems in 3 children. Substitution with antithrombin III was introduced in 15, with fibrinogen in 17 children because of low plasma concentration. In 21 patients treatment modifications according to decreasing of clotting factors concentration were done. Clotting problems strongly influence the treatment of children with ALL. Substitution therapy may improve the effectiveness of therapy.
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PMID:[Coagulation disorders during treatment with l-asparaginase preparations]. 1073 73

L-asparaginase is widely used in the treatment of acute lymphoblastic leukemia in children and adults. Use of L-aspa E. Coli as well as Erwinase is not possible in all cases because of the side effects, mainly allergic reactions and disfunction of pancreas. Recently, the new form of the enzyme PEG-L-asparaginase was introduced. Binding L-asparaginase E. coli to polyethylene glycol a decreased its toxicity, extended its plasma half-live, not significantly affecting the efficacy. The aim of the study was to examine the results of PEG-L-asparaginase administration in five children with acute lymphoblastic leukemia, and the symptoms of intolerance to L-aspa E. Coli or Erwinase. There were three children with newly diagnosed ALL and two children with first relapse of ALL, treated according to New York Protocol and BFM-90 Protocol for ALL relapses respectively. PEG-L-asparaginase (Oncaspar) was administered in the dose of 2500 IU/m2. According to the protocol four children received 11 courses of treatment with the full dose of the drug. The number of doses for individual patient varied from one to six. The short-lived nettlerash was observed in one patient during two subsequent infusions of the drug. Hydrocortisone and antihistamine drugs were administered. Treatment with PEG-asparaginase was discontinued in one child, who developed dyspnea, nausea, vomiting and face rash during the third dose of the drug. Oncaspar is the valuable drug, which enabled continuation of treatment according to protocol in four out of five children with bad tolerance to routinely used L-asparaginase preparations.
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PMID:[New possibilities of treatment with PEG-L-asparaginase in patients with acute lymphoblastic leukemia sensitized to l-asparaginase E.coli and erwinase]. 1073 74

Hereditary prothrombotic risk factors have been shown to increase the risk of venous thrombosis in children treated with the combination of E. coli asparaginase and steroids. In the present study the role of prothrombotic risk factors in children with ALL treated according to the COALL study protocol was investigated in 108 consecutively recruited childhood patients. The prevalence rates of prothrombotic risk factors [factor V G1691A mutation, the prothrombin G20210A variant, the TT677 methylenetetrahydrofolate reductase genotype, deficiencies of protein C, protein S, antithrombin, elevated lipoprotein (a)] in this cohort were within the range reported for healthy Caucasians, and comparable to previously reported data for other leukemic patients. Venous thromboembolism occurred in 3 of the 108 children (induction n = 1; reinduction n = 2: 2.8%), and none of these children carried a prothrombotic risk factor. The results of the present study, suggest that the role of hereditary and acquired disturbances of coagulation in the development of thromboses might depend on the treatment regimen.
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PMID:Prothrombotic risk factors in children with acute lymphoblastic leukemia treated with delayed E. coli asparaginase (COALL-92 and 97 protocols). 1089 35

MTT analysis has yielded data on the sensitivity of leukemia cells isolated from 64 patients with acute leukemia to the cytokines G-KSF?, GM-KSF, interferon-alpha 2b and their combined use with drugs, such as cytosar, vepeside, doxorubicin, vincrastine, L-asparaginase. The mean in vitro survival of leukemia cells in children with acute lymphoblast cell leukemia (ALCL) was 1.9 times less than that in acute myeloblast cell leukemia (AMCL) (p < 0.001), that in new cases of ALL was 2.3 times less than in relapses (p = 0.024). The stimulating effect of GM-KSF on the survival rates of leukemia cells was seen in 64.7% of patients with AML. That of GM-KSF was recorded in 21.4% of cases. The survival of lymphoblast cells isolated from children with ALL did not differ greatly in the absolute majority of cases (by more than 30%) in the presence of growth factor in the medium. The cytotoxicity of XII with medium growth factor decreased in most cases. However, some cases (more frequently in AML than ALCL) displayed a higher cytotoxicity of XII, particularly cytosar in the presence of G-KSF and GM-KSFG; LC50 of Ara-C decreased by 30% or more in the presence of growth factor in 36% of patients. Incubation with interferon alpha 2b caused a reduction in the survival of leukemia cells, which was more pronounced in children with ALL. Interferon-alpha 2b caused an increase in the cytotoxic effect of XII on leukemia cells in ALL to a greater extent; cytosar, vepeside, and doxorubicin enhanced the effect by 1.47, 1.39, and 2.35 times, respectively.
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PMID:[Study of tumor cells sensitivity in patients with acute leukemia to cytokines and their combined use with drugs in vitro by MTT analysis]. 1094 55


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