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)

L-Asparaginase was immobilized in microparticles of polyacrylamide. Such particles were then injected by intramuscular/subcutaneous, intraperitoneal, or intravenous routes into mice to investigate the immunological consequences of the immobilization. Entrapment of L-asparaginase in microparticles did not prevent the formation of antibodies in intensively treated animals. Intraperitoneal and intravenous injections of particles produced significantly higher antibody levels than soluble L-asparaginase. Antigen administered intramuscularly/subcutaneously in microparticles elicited, however, a weak immune response. Dependent on the route of administration, the particles may thus function as an adjuvant. A modified Arthus reaction in the foot pads of immunized mice indicated that antigenicity decreased when L-asparaginase was immobilized in microparticles. Injection of free L-asparaginase, intramuscularly/subcutaneously (2 x 20 IU) in the preimmunized mice produced no effects on the serum level of L-asparagine, whereas intramuscular/subcutaneous injection of L-asparaginase in microparticles produced a depression of the serum concentration. It is concluded that the intramuscular/subcutaneous injection of L-asparaginase in microparticles is the choice route of administration with respect to duration and the immunological reaction.
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PMID:Acrylic microspheres in vivo V: Immunological properties of immobilized asparaginase in microparticles. 621 69

Preparations of L-asparaginase made in the USSR, FRG and Japan were studied comparatively in 277 patients with acute lymphoblastic leukemia and lymphosarcomas. It was shown that the clinical characteristics of the preparation made in the USSR and the preparation (crasnitin) made in the FRG were identical. By the antileukemic action the preparation made in the USSR was superior to the preparation (leunase) made in Japan in the treatment of adult patients with such hemoblastosis forms. The effect of the three drugs in the treatment of children was analogous. The nature of the side effects of the three drugs was the same. However, their level was different. The allergenic effect of leunase on the patients was the most pronounced. L-Asparaginase made in the USSR and crasnitin are recommended for wide use in clinical practice.
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PMID:[Comparative evaluation of the clinical effectiveness of 3 preparations of E. coli L-asparaginase]. 638 31

The anti-tumor activity of L-asparaginase (EC. 3.5.1.1.) has been conclusively demonstrated. Its therapeutic application, however, has been hampered by its short clearance time in the circulation and high immunogenicity. In order to solve these problems, polyethylene glycol, a linear synthetic and non-immunogenic polymer, was introduced covalently into the amino groups in the enzyme molecule. Monomethoxypolyethylene glycol with molecular weight of 5000 was activated with cyanuric chloride to obtain activated PEGs [2, 4-bis (O-methoxypolyethyleneglycol)-6-chloro-s-triazine]. L-Asparaginase lost its immunoreactivity against its antibodies after the modification of 52 out of 92 amino groups in the molecule. This modified asparaginase retained 11% of its enzymic activity under the physiological condition. When the modified asparaginase was administered in rodents, it diminished the serum asparagine level and its enzymic activity persisted in the circulation 10 to 20 times longer than that of native enzyme. Furthermore, repeated injections of modified asparaginase did not induce any significant anti-asparaginase antibody production. Modified asparaginase showed a superior anti-tumor activity to the native counterpart irrespective of the presence of anti-asparaginase antibodies, when it was tested with murine Gardner lymphoma. This chemical modification should make it possible for the first time to repeatedly and effectively use L-asparaginase obtained from a bacterium.
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PMID:[Preparation of repeatedly and effectively usable L-asparaginase by a chemical modification]. 654 55

L-Asparaginase (L-asparagine amidohydrolase, EC 3.5.1.1) from Erwinia carotovora undergoes extensive dissociation from active tetramer to inactive monomers when freeze-dried. The monomeric state is stabilized by reconstitution of the freeze-dried enzyme with buffers of high pH and high ionic strength. Some compounds, particularly sugars and sugar derivatives, prevent dissociation on freeze-drying, whereas others, such as urea and chaotropic ions, increase dissociation. The effects of additives are not related to water retention. The dissociation is completely reversible on reconstitution at neutral pH, but the alkali-stabilized monomer only partially reassociates when the pH is brought back to neutrality.
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PMID:The effect of freeze-drying on the quaternary structure of L-asparaginase from Erwinia carotovora. 665 94

The acute effects of cyclophosphamide, vincristine, and L-asparaginase on the humoral and cell-mediated immune responses in dogs were evaluated. Dogs were given a single dose of cyclophosphamide (10 mg/kg of body weight, IV), a single dose of vincristine (0.025 mg/kg, IV), a single dose of L-asparaginase (400 U/kg, IV), or a combination of these drugs at the aforementioned dosages administered simultaneously. The total number of leukocytes decreased significantly (P = less than 0.05) on posttreatment day 3 in the cyclophosphamide-treated dogs. Antibody responses and lymphocyte blastogenesis were not affected. A transient lymphopenia on posttreatment day 1 was the only response seen in the vincristine-treated dogs. Antibody responses to sheep RBC and lymphocyte blastogenesis were suppressed in the L-asparaginase-treated dogs. L-Asparaginase did not affect the antibody response to bovine serum albumin or peripheral blood leukocyte counts. Suppressed antibody responses to sheep RBC and to bovine serum albumin, depressed lymphocyte blastogenesis, and decreased numbers of all peripheral blood leukocytes were seen in dogs given the 3 drugs in combination.
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PMID:Immunosuppressive effects of cyclophosphamide, vincristine, and L-asparaginase in dogs. 683 7

The antitumor effect of immobilized L-asparaginase was tested against lymphoid leukemia in mice with concomitant scanning of the L-asparagine level in serum. L-Asparaginase was immobilized in microspheres of polyacrylamide or polyacryldextran. These particles were used in C3H mice bearing the L-asparagine-dependent lymphoma (6C3HED). The tumor was maintained as an ascites tumor, 1 X 10(6) cells were injected intraperitoneally and on day 4 after inoculation, L-asparaginase was injected intramuscularly or intraperitoneally in microparticles. After injection of 5.0 IU ip of L-asparaginase in microparticles, partial remission was induced, generally, however, the cancer relapsed and killed the mice within 2-3 weeks. To obtain complete regression, it was necessary to inject 20 IU of L-asparaginase in microparticles intraperitoneally. The best therapeutic effect was obtained when the particles were administered intramuscularly. After injection of 5 IU the survival time was prolonged, but complete regression was not achieved. The best effect was obtained when the particles were given intramuscularly in two small doses (2.5 IU) at a 3-day interval. Such treatment induced complete regression; 10 out of 12 treated mice were completely cured and lived for several months. It is concluded that the L-asparagine level in serum has to be depressed to less than 20% of the normal level for at least 6-7 days to obtain complete regression of the tumor.
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PMID:Acrylic microspheres in vivo VI: antitumor effect of microparticles with immobilized L-asparaginase against 6C3HED lymphoma. 687 26

L-Asparaginase has been widely used for the treatment of acute lymphoblastic leukemia. Therapeutic and toxic effects in the central nervous system have been noted with systemic treatment. In order to better define the relationship between L-asparaginase administration and cerebrospinal fluid (CSF) asparagine levels, L-asparaginase and asparagine were measured in the CSF of rhesus monkeys following intrathecal and i.v. administration. Following intrathecal injection, the enzyme activity of Escherichia coli L-asparaginase in the CSF demonstrated a more rapid terminal half-life than did that of 111In-labeled diethylenetriaminepentaacetic acid, a marker of CSF bulk flow [4 +/- 0.7 (S.D.) hr versus 5.8 +/- 0.2 hr]. Intrathecal injection of E. coli asparaginase resulted in complete depletion of CSF asparagine for at least 5 days. A similar period of CSF asparagine depletion was observed following i.v. administration of L-asparaginase. Similar results were found in seven patients undergoing systemic L-asparaginase therapy. The minimal plasma level of L-asparaginase necessary to deplete CSF asparagine in both species was 0.1 IU/ml. Two other enzymes, Erwinia L-asparaginase and succinylated Acinetobacter glutaminase-asparaginase, were cleared from the CSF at the same rate as bulk flow. These data indicate that systemic L-asparaginase therapy may be a feasible means of treating central nervous system involvement in patients with acute lymphoblastic leukemia and that there is no therapeutic advantage to using intrathecal L-asparaginase.
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PMID:L-asparaginase pharmacokinetics and asparagine levels in cerebrospinal fluid of rhesus monkeys and humans. 689 81

L-Asparaginase is commonly used for induction therapy of acute lymphocytic leukemia of childhood. Severe clinical bleeding secondary to clotting dysfunction has not been previously reported. We observed intracranial hemorrhagic infarcts with focal seizures and hemiparesis associated with clotting abnormalities, including severe hypofibrinogenemia, probably the result of L-asparaginase administered during induction therapy of acute lymphocytic leukemia.
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PMID:Intracranial hemorrhage and focal seizures secondary to use of L-asparaginase during induction therapy of acute lymphocytic leukemia. 693 31

L-Asparaginase therapy for childhood acute lymphoblastic leukemia causes deficiencies of plasma hemostatic proteins, especially antithrombin, plasminogen, and fibrinogen. Severe thromboses and hemorrhages occurred in 18 children receiving vincristine, prednisone, and asparaginase therapy for ALL. Thirteen children had intracranial thrombosis or hemorrhage, four had extremity thrombosis, and one had both an intracranial hemorrhage and an extremity thrombosis. These events occur characteristically in the third and fourth weeks of therapy during or just after a three-week course of L-asparaginase. Symptoms of headache, obtundation, hemiparesis, and seizure were common for the intracranial events: local pain, swelling, and discoloration were common for the extremity thromboses. These complications have been recognized in 1 to 2% of children undergoing induction therapy which includes asparaginase.
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PMID:A syndrome of thrombosis and hemorrhage complicating L-asparaginase therapy for childhood acute lymphoblastic leukemia. 695 21

A series of studies were undertaken by the Childrens Cancer Study Group between 1968 and 1972 to evaluate the optimum schedule and dosage of L-asparaginase as a single agent in induction and maintenance of children with previously treated acute lymphocytic leukemia. Six different dosages of enzyme were administered (3600-840,000 IU/4 wk/m2). The optimal dose of L-asparaginase was found to be 12,000 IU/m2 given three times per week for a total dose of 144,000 IU/m2. Sixty-three percent of children treated with this dosage achieved a bone marrow remission. The intramuscular method of administration is as effective and produced less significant sensitivity reactions than the intravenous method. Reinduction, after an unmaintained remission, with L-asparaginase was possible in 32% of the cases. L-Asparaginase used as a maintenance agent did not result in a significant increase in remission duration when compared to no maintenance therapy. However, patients who received L-asparaginase maintenance had a median remission duration of 66 days as compared to 41 days for the no-maintenance group.
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PMID:L-Asparaginase as a single agent in acute lymphocytic leukemia: survey of studies form Childrens Cancer Study Group. 704 73


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