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

L-Asparaginase, an effective agent in the treatment of acute lymphoblastic leukemia, may induce a diabetic state. The pathogenesis of the diabetogenic effect was studied in cultured pancreatic islets. Mean serum concentrations in three children with acute lymphoblastic leukemia were 2.4 U/mL (range 1.4-4.5) before and 31.5 U/mL (range 18.6-51.8) immediately after an intravenous injection of 1000 U/kg L-asparaginase. Glucose-induced insulin release from pancreatic islets of rat and man was measured after 3 and 7 days of culture in media with or without clinically relevant concentrations of Escherichia coli L-asparaginase (0.01-100 U/mL). After culture, the remaining insulin, glucagon, and DNA in the islets were determined. After 7 days of culture of adult rat or human islets, both the accumulation of insulin in the medium and the content of insulin and glucagon in the islets were significantly reduced in the presence of 100 U/mL L-asparaginase compared with controls. Addition of 10(-6) M hydrocortisone to the culture medium enhanced this effect. In newborn rat islets a significant reduction in insulin release and content was observed already in the presence of 0.1 U/mL asparaginase, whereas the glucagon content was unchanged. Removal of the drug resulted in partial recovery of the insulin secretion. To elucidate the mechanisms of of action of the drug, insulin biosynthesis was studied in islets cultured in asparagine-free medium with or without asparaginase. No difference in biosynthesis was seen between media with or without asparagine, whereas 0.1 U/mL asparaginase caused about a 50% reduction under both conditions.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Direct long-term effects of L-asparaginase on rat and human pancreatic islets. 267 5

L-Asparaginase activity reaches maximal values at the stationary phase of growth of Tetrahymena pyriformis and fluctuates upon the growth conditions and the composition of the medium. Most of the L-asparaginase activity (80%) is associated with the endoplasmic reticulum, and the remaining with the pellicles. Detergents either alone or in combination with NaCl up to 0.5 M concentration failed to solubilize L-asparaginase. Solubilization can be accomplished by means of either the chaotropic agents KSCN and NaClO4, or 0.1 M sodium phosphate buffer pH 8.0, following pretreatment of the particulates with 2% w/v Triton X100. L-Asparaginase has been purified to near homogeneity by hydrophobic and gel filtration chromatography. The native enzyme has a relative molecular weight of 230,000. It is a multiple subunit enzyme, with subunit size of 39,000. Its isoelectric point is at pH 6.8. It acts optimally at pH 8.6 with a Km of 2.2 mM. It does not hydrolyse L-glutamine and its reaction is inhibited competitively by D-aspartic acid and D-asparagine as well as by L-asparagine analogues with substituents at the beta position.
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PMID:Purification and properties of a membrane-bound L-asparaginase of Tetrahymena pyriformis. 313 90

L-Asparaginase, commonly used in combination chemotherapy in the treatment of acute lymphoblastic leukemia, has been associated with hemorrhagic and thrombotic cerebrovascular events. Thrombosis of the cerebral veins or dural sinuses is common, and may be associated with either hemorrhage or infarction. This syndrome generally occurs after a few weeks of therapy, and may occur after L-asparaginase therapy is completed. Complications appear to result from depletion of plasma proteins involved in coagulation and fibrinolysis. We now report two additional cases of cerebrovascular complications associated with L-asparaginase therapy. We review the previously reported cases and discuss the clinical presentation, pathophysiology, and suggested treatment of this syndrome.
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PMID:Cerebrovascular complications of L-asparaginase therapy. 327 3

The morbidity and mortality due to short-term adverse effects of antileukemic chemotherapy were studied in a follow-up of 100 children with ALL on a conventional regimen. Severe toxic adverse effects were observed in 20%, and they were fatal in 3% of the children. Moderate or mild adverse effects were seen in 68%, and only 12% remained without noticeable side effects. The drugs responsible for the severe adverse effects were vincristine, L-asparaginase, and intrathecal methotrexate. L-Asparaginase was the most hazardous individual agent, being responsible for 1 and probably contributing to other 2 induction deaths. The toxicity as a whole of this conventional ALL chemotherapy regimen could be considered acceptable, except for the mortality, since the adverse effects were temporary and reversible.
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PMID:Toxicity of conventional ALL chemotherapy: incidence of short-term adverse effects in 100 children. 347 66

L-Asparaginase (EC 3.5.1.1) inhibited respiration in sensitive, but not resistant, lines of murine lymphoma 6C3HED. Glucose, in these tumor lines, was principally converted to lactate, and very little was oxidized in the citric acid cycle or hexose monophosphate shunt. The cells derived 70-80% of their respiratory CO(2) from glutamine or glutamate. Asparaginase had no effect on the pattern of glucose utilization. The differential effect on oxygen consumption may result from the absence of asparagine synthetase in sensitive cells. Respiration may be inhibited by accumulation of the aspartate, the product of glutamate oxidation. Resistant lymphoma cells remove aspartate by converting it to asparagine. Sensitive cells, which lack asparagine synthetase, cannot make asparagine.
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PMID:Glutamate oxidation of 6C3HED lymphoma: effects of L-asparaginase on sensitive and resistant lines. 453 Feb 80

L-Asparaginase was used to treat 40 patients with acute leukaemia or lymphosarcoma. Fifteen with acute lymphoblastic leukaemia either untreated or in relapse after previous therapy were given "Squibb," "Bayer," or "Porton" L-asparaginase. Five of these patients had complete remission of their disease, and four had good partial remission. Eleven patients with acute myeloid leukaemia were treated for a short period with L-asparaginase alone. None of them went into remission though a pronounced fall in the numbers of circulating white cells was seen. Six patients with lymphosarcoma received L-asparaginase, two of them having good partial remissions.The toxic side-effects of the L-asparaginase from the three sources seemed to vary, and L-asparaginase from Erwinia carotovora appeared to be antigenically different from the enzyme produced by Escherichia coli.The way in which leukaemic cells become resistant to the action of the enzyme requires further investigation. To overcome this resistance asparaginase should be used in combination with other drugs in the treatment of acute leukaemia.
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PMID:L-asparaginase in treatment of acute leukaemia and lymphosarcoma. 490 33

Of 28 coliforms, five strains of Escherichia coli were particularly active in elaborating L-asparaginase 2, the form of the enzyme useful in the treatment of some forms of cancer. Since it is advantageous to start purification of the enzyme from highly active cells, cultural conditions necessary for good growth and high enzyme yield have been studied. Gentle aeration proved suitable for good growth as well as high enzyme content. Stationary cultures gave poor growth, whereas vigorous aeration gave good growth but resulted in a marked decrease in the enzyme content of the cells. L-Asparaginase 2 has been purified about 40-fold by a combination of ammonium sulfate and ethyl alcohol precipitations.
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PMID:Conditions for the production of L-asparaginase 2 by coliform bacteria. 490 96

Fifty percent of New Zealand white rabbits became profoundly weak, had generalized seizures and died between 22 and 47 hours after an intravenous injection of 1000 IU/kg of L-asparaginase. The biochemical correlate of this syndrome is severe hypocalcemia associated with marked, single cell, oxyphilic necrosis in the parathyroid glands. Although survivors remained clinically well, they also developed hypocalcemia and parathyroid necrosis but to a lesser degree. Rabbits given an equivolumetric amount of saline did not develop alterations in any of these parameters. L-Asparaginase, therefore, exerts a direct toxic effect on the parathyroid glands of rabbits. The implications of this finding for man are briefly discussed.
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PMID:Parathyroid necrosis and hypocalcemic tetany induced in rabbits by L-asparaginase. 505 53

L-Asparaginase in agouti serum and in extracts from Escherichia coli inhibits the early wave of mitosis occurring in rat liver approximately 30 hours after hepatectomy, but even with continued treatment of the animal the later wave at 50 hours is not inhibited. This result differs from the permanent inhibition of growth which asparaginase causes in various tumors.
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PMID:L-asparaginase: inhibition of early mitosis in regenerating rat liver. 533 34

Fibrinolytic factors were assessed during L-asparaginase administration, to study whether their changes may predispose to a haemorrhagic or thrombotic diathesis. The total level of alpha 2-antiplasmin declined, as well as the ratio of the plasminogen-binding form of alpha 2-antiplasmin to the non-plasminogen-binding form. After cessation of L-asparaginase administration, the ratio increased to 1.6 times that of the pretreatment value. These data indicate that the plasminogen-binding form of alpha 2-antiplasmin is the form primarily synthesized in vivo. L-Asparaginase therapy reduced plasma levels of plasminogen and histidine-rich glycoprotein ( HRG ) and influenced the equilibrium between HRG , plasminogen and HRG -plasminogen complex, with a more pronounced decrease of plasminogen (62% +/- 8) and HRG (76% +/- 11) in comparison to the free-plasminogen levels (51% +/- 6). alpha 2-Macroglobulin was only slightly influenced by L-asparaginase and may consequently play a more pronounced role in inhibition. This is suggested by moderate declines in functional tests of plasmin, urokinase and tissue activator inhibition by patients plasma, and by the ratio of inhibition of these enzymes over alpha 2-antiplasmin. Thus the bleeding tendency described during L-asparaginase therapy can be ascribed not only to a temporary deficiency of coagulation factors but also to temporary alpha 2-antiplasmin deficiency.
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PMID:The influence of L-asparaginase therapy on the fibrinolytic system. 620 49


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