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)

Use of L-asparaginase by the extracorporeal route in the therapy of acute lymphoblastic leukemia (ALL) has been proposed. Results, however, are not so satisfactory as i.v. administration of this enzyme, because the levels of L-asparagine do not fall for a sufficient length of time due to the antagonistic action of the L-asparagine-synthetase. To avoid the L-asparagine rebound we have utilized, by extracorporeal route, L-glutaminase together with L-asparaginase, in order to reduce L-asparagine and L-glutamine levels. We have therefore performed a series of experiments in vitro and in vivo either using L-asparaginase alone or together with L-glutaminase. Results show that, contrary to what happens when L-asparaginase is used alone, L-asparagine levels decrease and remain low even after 24 hours from the treatment, when L-glutaminase is added to the system. Thus a lowering of L-glutamine levels, which seems to play an important role in the therapy of ALL, is obtained.
Int J Artif Organs 1981 Sep
PMID:L-glutaminase and L-asparaginase by extracorporeal route in acute lymphoblastic leukemia therapy. 694 66

Phase II clinical trials of L-asparaginase of leunase manufactured by "Kyowa" (Japan) was performed in cooperation by 5 institutions of the USSR on 49 patients with various forms of hemoblastosis, including 15 patients aged 1 to 15 and 34 patients aged 16 to 75. The drug was used in a daily dose of 200 IU per 1 kg body weight administered as intravenous drips daily for 2--3 weeks. The daily dose was divided into 2 doses administered at an interval of 12 hours. The efficiency of the treatment did not depend on the patients' sex. Significant efficiency of leunase was observed in children with acute lymphoblastic leukemia (85.7 per cent). The use of the drug in treatment of adults with systemic malignant blood affections was less effective. Some effects recorded in patients with generalized forms of hematosarcoma were transient. The following side effects were noted: nausea, vomiting in 8 children and 13 adults, allergic reactions in the form of pruritus and rashes in 8 adults, impairment of liver and pancreatic functions in 2 children and 1 adult. Acute pancreatonecrosis was recorded in one child. The effect on the peripheral blood was insignificant. Leunase has probably no advantages as compared to other L-asparaginase preparations.
Antibiotiki 1980 Sep
PMID:[L-asparaginase study results (phase II of the clinical trials)]. 699 70

The relationship between conformation change and activity of E. coli L-asparaginase has been studied with circular dichroism spectra and microcaloric methods. In many papers, it has been pointed out that the active site of L-asparaginase is closely related to tyrosyl residues. The present authors have studied the effects of L-cysteine on the activity and the conformation of L-asparaginase with UV difference spectra and kinetic methods. Moreover, we have studied the space arrangement of tyrosyl residues in the enzyme molecule. The results show that every enzyme molecule contains about 56 tyrosyl residues, 20 of which are in the hydrophobic core of the enzyme molecule, another 20 at the surface of the enzyme molecule, and the rest in the rifts and hollows of the enzyme molecule. Meanwhile, further study has also been made to determine the relationship between the changes of the enzyme activity and the ionization of tyrosyl residues as well as their chemical modification. By Zou Chenglu's graphical method we have proved that two tyrosyl residues at the surface of the enzyme molecule are the essential groups.
Sci Sin 1981 Sep
PMID:Tyrosine micro-region of E. coli L-asparaginase. 702 10

Cultured human pancreatic carcinoma cells (MIA PaCa-2) have been shown previously to be very sensitive to E. coli L-asparaginase (EC II). The present studies have demonstrated that another enzyme, Acinetobacter glutaminase-asparaginase (AGA) is much more effective in inhibiting cell growth. At the concentration of 0.0025 U/ml of AGA activity the enzyme totally inhibited cell growth, whereas the EC II with the same concentration did not show any effect. The inhibition of cell growth correlated well with inhibition of protein and glycoprotein synthesis. The addition of L-glutamine at the concentration of 1 mM completely reversed the inhibition of protein synthesis. Similarly, the addition of L-glutamine at the concentration of 3 mM daily on 3 successive days after adding AGA resulted in significant reversal of growth inhibition. The results of this study indicate that the action of AGA on MIA PaCa-2 is, to a great extent, exerted through its L-glutaminase activity.
In Vitro 1982 Sep
PMID:Sensitivity of cultured pancreatic carcinoma cells to Acinetobacter glutaminase-asparaginase. 717 49

The importance of five tyrosine residues of Escherichia coli asparaginase II (EcA2) for catalysis and protein stability was examined by site-directed mutagenesis, chemical modification of wild-type and variant enzymes, and by thermodynamic studies of protein denaturation. While the tyrosine residue Y25 is directly involved in catalysis, the hydroxyl groups of residues Y181, Y250, Y289 and Y326 are not necessary for EcA2 activity. However, residues Y181 and Y326 are crucial for stabilization of the native EcA2 tetramer. pH titration curves showed that the active-site residue Y25 has a normal pKa while the C-terminal Y326 is unusually acidic. 1H-NMR signals of a peculiar ligand-sensitive tyrosine residue were assigned to Y25. These and other data suggest that a peptide loop (residues 14-27) which shields the active site during catalysis is highly flexible in the free enzyme.
Eur J Biochem 1994 Sep 01
PMID:States and functions of tyrosine residues in Escherichia coli asparaginase II. 792 69

This study shows that the antigenicity of Erwinia chrysanthemi L-asparaginase can be reduced by site-directed mutagenesis. Ten B-cell epitopes of the enzyme were identified using synthetic hexapeptides and polyclonal antisera from rabbits and mice. The region 282GIVPPDEELP292 near the C-terminus was an immunodominant epitope. Binding of two hexapeptides (283IVPPDE288 and 287DEELPG292) to the antibodies was dependent on Pro285, and Pro286, since their replacement by almost any other amino acid resulted in reduced binding. The other residues were less important for binding the antibodies, as binding was relatively unaffected by amino acid substitutions. Three site-directed mutant enzymes, P285T (proline-285-->threonine etc.), P286Q and E288A, were expressed in Escherichia coli. The purified enzymes had subunit M(r) values of 35,000. The pI values of P285T, P286Q and the wild-type enzymes were 8.6, and that for the mutant E288A was 9.2. The kcat. and Km values for the mutants P286Q and E288A with L-asparagine and L-glutamine were comparable with those of the wild-type enzyme. The Km values for the mutant P285T with both substrates was similar to that of the wild-type enzyme, whereas the kcat. was reduced by 2-fold with L-asparagine and by 4-fold with L-glutamine. The change proline-->threonine reduced the antigenicity of the enzyme by 8-fold, as shown in sandwich e.l.i.s.a.s. using monoclonal antibodies raised against the wild-type enzyme.
Biochem J 1994 Sep 15
PMID:Erwinia chrysanthemi L-asparaginase: epitope mapping and production of antigenically modified enzymes. 794 21

Fifty five children diagnosed as having high-risk acute lymphoblastic leukemia (ALL) between 1985 and 1988 were treated with protocol AL851. The agents used in the protocol were as follows: induction therapy: vincristine (VCR), prednisolone, daunorubicin (DNR) and l-asparaginase, consolidation therapy: an intermediate-dose methotrexate (MTX), central nervous system (CNS) leukemia prophylaxis: intrathecal MTX and 24Gy cranial irradiation, reinduction therapy: VCR, adriamycin, dexamethasone and high dose cytarabine (AraC), maintenance therapy: 6-mercaptopurine, cyclophosphamide, MTX, DNR, VCR and AraC. Patients received chemotherapy for 3 years after achieving complete remission (CR). CR was obtained in 51 patients (92.7%). Twenty-four of them relapsed after achieving CR (bone marrow 16, CNS 3 and testis 5). At median follow-up of 79 (range 64-102) months, the estimated 8-year disease free survival rate was 49.1 +/- 6.7%. Four patients relapsed at bone marrow during the first 6 months of the treatment, indicating that more intensive combination chemotherapy should be included in earlier stage of the protocol. The high incidence of testicular relapse (14.3% in boys) suggests that high-dose MTX or AraC should be needed for improvement of the prognosis of high-risk ALL patients.
Rinsho Ketsueki 1994 Sep
PMID:[Clinical trial of protocol-AL851 for children with high-risk acute lymphoblastic leukemia. Kyushu Yamaguchi Children's Cancer Study Group (KYCCSG)]. 796 55

Fifty consecutive adult patients with acute lymphoblastic leukemia (ALL) were treated with an intensive cyclical chemotherapy and the mean received dose of individual cytotoxic drug was retrospectively studied. The median age was 28 years. Twenty-one (43%) had white blood cell (WBC) count over 30 x 10(9)/l. Of the 26 patients with successful cytogenetic studies, ten (28%) had unfavorable clonal chromosomal abnormalities (four Philadelphia chromosome, six others). A high complete remission (CR) rate (86%) was achieved. This was associated with delivery of 100% of the planned dosage of vincristine, prednisone, and daunorubicin at induction. Dose reduction of asparaginase, the fourth drug in the induction protocol, was recorded in 20 (40%) patients. The CR rate of these patients was not adversely affected. Dose reduction was recorded during consolidation (38 of 43 remitters) and maintenance (18 of 20 remitters) as a result of treatment toxicity. The mean received dose of teniposide, Ara-C, asparaginase, mercaptopurine, and methotrexate was 73% (SD 7%), 73% (SD 7%), 62% (SD 41%), 65% (SD 15%) and 73% (SD 17%) of the planned dosage, respectively. The 5-year overall survival and leukemia-free survival (LFS) were 11% (95% CI: 0-27%) and 13% (95% CI: 0-26%), respectively. Even standard-risk patients had 4-year LFS of only 26% (95% CI: 0-57%). Among 36 remitters not withdrawn from consolidation, there were 29 treatment failures after a median follow-up of 42 months; 25 (86%) of these were leukemia relapse, three (10%) were toxic death during consolidation, and one patient (4%) died from therapy-related myelodysplastic syndrome. We postulate inadequate drug delivery during postremission therapy contributed to the high relapse rate in the whole group as well as the standard-risk patients.
Leukemia 1994 Sep
PMID:Poor outcome of intensive chemotherapy for adult acute lymphoblastic leukemia: a possible dose effect. 776 60

Fifty two adults (aged 15 to 66 years) with newly diagnosed acute lymphoblastic leukemia (ALL, n = 47) or lymphoid blast phase chronic myelogenous leukemia (Ly-CML, n = 5) were managed with three distinct protocols containing idarubicin at a cumulative dose of 36, 20, and 10 mg/m2, respectively, plus vincristine, L-asparaginase, and prednisolone (IVAP-1, -2, -3). IVAP-1 was highly toxic and gave a low complete remission (CR) rate (7/17, 41%). Nine patients died of complications while severely neutropenic, and one had resistant disease. In contrast, 24 of 28 patients subsequently treated with IVAP-2 achieved a CR (86%, p 0.005), the rate of both hematological and extrahematological toxicity being significantly reduced compared with IVAP-1 (p < 0.05). With IVAP-3, 6/7 patients aged > 60 years achieved CR. IVAP-2 with total idarubicin 20 mg/m2 is a very effective and well tolerated regimen for the initial treatment of adults with ALL.
Leuk Lymphoma 1993 Sep
PMID:Idarubicin in the initial treatment of adults with acute lymphoblastic leukemia: the effect of drug schedule on outcome. 822 Jan 42

From 1975 to 1989, 71 acute lymphoblastic leukemia patients aged 15 to 81 years (median 46 years) were treated at Jichi Medical School. Fifty-eight patients (81.7%) achieved complete remission (CR). Median CR duration was 219 days, and the probability of being in continuous CR at 3 years was 8.9%. Median survival was 462 days, and the probabilities of being alive at 3 and 5 years were 19.8% and 7.3%, respectively. The new regimen introduced from 1987 consisted of remission induction with L-asparaginase, daunomycin, vincristine and prednisolone, followed by intensive consolidation and maintenance. However, the treatment failed to improve outcome. The factor unfavorable for achieving early CR after first-line treatment regimen was the presence of myeloid antigen, and that for achieving final CR after second-line treatment regimen was advanced age. The factors unfavorable for remission duration were high leukocyte count and late CR. Those unfavorable for survival were advanced age and elevated blood urea nitrogen. Further improvement in the design of new protocols which include the use of several cytokines and autologous bone marrow transplantation may result in prolonged disease-free survival.
Gan To Kagaku Ryoho 1993 Sep
PMID:[Treatment of 71 adult acute lymphoblastic leukemia]. 837 76


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