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:3.5.1.1 (asparaginase)
2,695 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Of 4 lines of myelogenous rat leukemias induced by N-nitrosobutylurea (NBU), DBLA-6 was selected as a screening model for antileukemic agents because of the following characteristics: a) High transplantability either by intravenous (i.v.) or intraperitoneal (i.p.) inoculation; b) linear relationship between inoculum size and survival time; c) marked increase of leucocyte counts in the peripheral blood as the tumor progresses after intravenous inoculation. To investigate reliability in its predicting clinical efficacy, its sensitivity to known antileukemics was studied. To determine the effects, a change of leucocyte counts in the peripheral blood together with the prolongation of life span was checked in the following systems; i.v.-i.v. (i.v.-inoculation, i.v.-injection), i.v.-i.p., i.p.-i.p., i.p.-i.v. Fifty percent cure was obtained with Vincristine, Vinblastine, Daunorubicin, 6-Mercaptopurine, and alkylating agent 838D or 864T. The success of treatment was measured by decrease of leucocytes. Methotrexate, cytosine arabinoside (Ara-C), and cyclophosphamide showed only poor effects, and Mitomycin C, L-asparaginase, and Bleomycin were ineffective. In addition, the chemotherapeutic effects of Vincristine and 864 on this leukemia were quite dependend both on the route of drug injection and on the site of tumor inoculation. Subsequently, our studies are being extended to cover the correlation between drug distribution and tumor localization or dissemination.
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PMID:Sensitivity of DBLA-6 leukemia of rats to known antitumor agents in relation to their clinical effects. 116 99

Parameters of thyroid function were measured in nine children during induction therapy for acute lymphoblastic leukemia (ALL). Seven patients were reevaluated during the late intensification phase. Vincristine, anthracycline drugs (daunorubicin and adriamycin), corticosteroids, and L-asparaginase were used in the two phases of therapy. During induction, L-asparaginase (5,000 U/m2) was given daily on days 1-21. During late intensification, the drug was given on days 1, 4, 8, and 11 (10,000 U/m2). During induction, total T4 significantly decreased from 10.1 +/- 2.3 to 4.0 +/- 1.0 micrograms/dl, FT4 decreased from 1.4 +/- 0.3 to 0.7 +/- 0.2 ng/dl, total T3 decreased from 134 +/- 32 to 57 +/- 21 ng/dl, and thyroxine binding globulin (TBG) decreased from 2.1 +/- 0.6 to 0.8 +/- 0.3 mg/dl. During late intensification therapy, significant decreases in T3 (from 180 +/- 26 to 93 +/- 40 ng/dl) and TBG (from 1.9 +/- 0.5 to 1.1 +/- 0.5 mg/dl) were observed, but there were no significant changes in T4 and FT4. We conclude that during induction, the impairment of thyroid function is attributable to L-asparaginase, whereas during late intensification, low T3 and low TBG is due to glucocorticoid administration.
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PMID:Thyroid function during L-asparaginase therapy in children with acute lymphoblastic leukemia: difference between induction and late intensification. 151 Jan 86

Relatively nonmyelotoxic drugs and drug combinations were investigated for their ability to eliminate malignant cells from human bone marrow. In vitro 90% inhibitory concentration (IC90) doses were established on granulocyte macrophage colony-forming units (GM-CFU) in culture of bone marrow by using the GM-CFU assay for the following drugs: 4-hydroperoxycyclophosphamide (4-HC), Adriamycin, L-asparaginase, bleomycin, hydrocortisone, VP-16, spirogermanium, Taxol, and vincristine. The leukemic cell kill efficiency of these drugs at IC90 doses was compared with that of 4-HC on acute lymphoid leukemia (ALL) cell lines by using the limiting-dilution assay. Under these conditions, no single drug was superior to 4-HC. To increase the in vitro effect in leukemic cell kill, combinations of vincristine with hydrocortisone, Adriamycin, VP-16, and 4-HC were investigated. Vincristine at 1 to 5 micrograms/mL increased the marrow cytotoxicity of hydrocortisone, Adriamycin, and VP-16, but it was protective (subadditive) with 4-HC. Vincristine and 4-HC in combination was additive to supraadditive on ALL cell lines, increased the leukemic cell kill by one to two logs above 4-HC alone at IC90 doses (P less than .05), and was not affected by the addition of excess marrow cells. The recommended doses for chemopurging in clinical studies are vincristine, 1 to 5 micrograms/mL, plus 4-HC, 5 micrograms/mL.
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PMID:Evaluation of drugs for elimination of leukemic cells from the bone marrow of patients with acute leukemia. 244 78

Forty-five patients with acute lymphoblastic leukemia of standard risk who were treated with the same protocol of therapy are presented. Induction therapy consisted of Vincristine (5 doses), L-asparaginase (10 doses) and prednisone. Complete remission was attained in 43 cases (95%). Two different methods of CNS prophylaxis were used; radiotherapy of the skull (18 Gy) associated with intrathecal methotrexate and intermediate dose intravenous methotrexate (1 g/M, 12 dose) with simultaneously intrathecal methotrexate. With a mean follow-up time of 28 months in group A and 35 Mo in group B, 82% and 75% respectively remain in continuous complete remission (p: NS). One case of meningeal leukemia was detected in each group. There patients in group A (13.6%) and four in group B (20%) suffered a bone marrow relapse. Actuarial survival rate at 36 months were 76 among the patients in group A and 83% in group B. Our results indicate that the two methods of CNS prophylaxis are both effective and in this series we have not observed any decrease in the bone marrow relapse rate when intermediate dose methotrexate was used.
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PMID:[Acute lymphoblastic leukemia of standard risk: preliminary results obtained with protocol LL-IV-81]. 348 21

Human bone marrow cells from 20 patients as well as the permanent human B-cell lines RPMI 1788, Raji, Daudi, T-cell lines Molt, CEM, Jurkat and the promyelocytic line HL 60 were assayed by means of a newly developed in vitro flow cytometric cytostatic drug assay. The cells were exposed to cytosine-arabinoside, L-asparaginase, daunorubicin, prednisone or vincristine. Surviving cells were stained after an incubation period of 2 to 7 days with esterase and pH-indicator dye ADB (1,4-diacetoxy-2,3-dicyanobenzene), dead cells with DNA-dye PI (propidium iodide). Dose-response curves were established using percent surviving cells. It was possible to evaluate bone marrow samples from 16 out of 20 patients. Seven samples were leukemic (acute myeloid leukemia (AML) n = 6, Non-Hodgkin's Lymphoma (NHL) n = 1). Nine samples were from patients either in complete remission or with benign diseases. Daunorubicin and cytosine-arabinoside were cytotoxic in both groups, whereas vincristine was effective mainly in the leukemic group (p less than 0.05). There was significant heterogeneity in the reactivity of AML-marrow cells from different patients to different drugs. The cell lines exhibited different patterns of sensitivity. Vincristine arrested cells in G2/M-phase, cytosine-arabinoside caused an increase of cells in the S-phase.
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PMID:Cytostatic drug testing in human leukemias by means of multiparametric flow cytometry. 367 21

The toxicity of Salmonella typhosa 0901 W endotoxin for BALB/c mice was potentiated by the administration of 375 mg of cyclophosphamide per kg, 16 mg of daunomycin per kg, 80 mg of methotrexate per kg, 8 mg of pactamycin per kg, 20 mg of polyinosinic-polycytidylic acid per kg, 1,000 mg of procarbazine per kg, and 1 or 4 mg of vincristine per kg. l-Asparaginase (20,000 units per kg) failed to potentiate endotoxin. Sedation following administration of 45 mg of pentobarbital per kg was prolonged in mice that had received 20,000 units of l-asparaginase per kg, 4 mg of daunomycin per kg, 120 mg of methotrexate per kg, 8 mg of pactamycin per kg, 10 mg of polyinosinic-polycytidylic acid per kg, 500 mg of procarbazine per kg, 2 mg of vincristine per kg, 2 mg of endotoxin per kg, or multiple doses of endotoxin. Mice pretreated with multiple endotoxin doses experienced a significant reduction in their lethal responses due to vincristine-endotoxin combinations; however, endotoxin-pretreated mice were more susceptible to vincristine alone than were normal mice. Simultaneous administration of 1 or 2 mg of vincristine per kg and 1 mg of endotoxin per kg produced greater lethality than sequential regimens. Pretreatment of mice with 65 mg of phenobarbital per kg on 4 consecutive days protected against vincristine-endotoxin combinations. Liver homogenates prepared from mice exposed previously to vincristine were capable of inactivating endotoxin. Vincristine lethality was increased by simultaneous administration of heat-killed cells of Pseudomonas aeruginosa isolated from mouse feces.
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PMID:Enhanced toxicity for mice of vincristine and other chemotherapeutic agents with Salmonella typhosa endotoxin and Pseudomonas aeruginosa. 421 44

The recent development of chemotherapy in the treatment of cancer and leukemia requires that all practitioners involved have a thorough knowledge of the sometimes life-threatening side-effects of chemotherapeutic agents. All these agents, whether used alone or in a combination, carry a risk because of their lack of specificity which make active on normal cells, especially those with a rapid turn-over such as the hematopoietic cells or the cells of the digestive tract. Prior to the prescription of a chemotherapeutic regimen, the acceptable risk must always be clearly defined, according to the seriousness of the disease and to the patient's age, physical condition and psychological status. During the course continuous monitoring adjusted to the specific toxicity of the agents used is requisite. More or less prominent asthenia and weight loss are common, as the result of various physiopathological mechanisms. Digestive disorders may consist only of nausea and emesis or include mucosal lesions with diarrhea as the main feature. Vincristine and vindesine are responsible for constipation. Hepatic toxicity, which is less common, is usually due to L-asparaginase. Transient hair loss is the most frequent cutaneous side-effect. Hyperpigmentation, photosensitivity, nail lesions, cellulitis and ulcerations may occur, as well as specific lesions with bleomycin. High fever during injection often occurs with this last agent.
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PMID:[Complications of antitumor and antileukemic chemotherapy. 1]. 629 36

Increasingly vigorous chemotherapy of cancer including primary and metastatic central nervous system disease has resulted in prolonged good-quality survival. However, there has been an associated increase in neurotoxicity from both radiation therapy and chemotherapy. All classes of chemotherapeutic agents contain drugs that are potentially neurotoxic, often only at high doses. Mechlorethamine, the first nitrogen mustard, is not neurotoxic at conventional dosage, but at high doses, it may produce both an acute and a delayed encephalopathy. Methotrexate administered intrathecally often induces reversible aseptic meningitis, but chronic administration, either intrathecally or high-dose intravenously, may produce fatal leukoencephalopathy. 5-Fluorouracil at high dosage may cause cerebellar ataxia, but may also do so at low dosage when combined with thymidine infusions. Cytosine arabinoside at high dosage may also produce cerebellar ataxia. Vincristine produces a peripheral neuropathy, and less commonly causes both autonomic and cranial neuropathy. The enzyme L-asparaginase can produce a dose-related reversible encephalopathy. BCNU, now the mainstay of glioma chemotherapy, may combine with radiation to produce long-term cerebral atrophy. Both intracarotid and high-dose intravenous BCNU administration may cause encephalopathy. Several other chemotherapeutic agents have also been reported to cause neurotoxicity under certain circumstances.
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PMID:Neurological complications of antineoplastic therapy. 638 4

Vincristine was inadvertently injected into a thigh of three children. In each case the accident occurred as a result of the mixing of a syringe containing vincristine with a syringe of L-asparaginase which the patient was scheduled to receive on the same day. Within minutes, each patient was treated topically with cold compresses and the area was infiltrated with a solution of 8.4% sodium bicarbonate. Only one patient had discomfort of the thigh after the injection, none of the patients have had any sequelae, either acute or delayed. Measures to avoid mistaken injection of vincristine for asparaginase are readily achievable and have prevented recurrences of intramuscular vincristine administration at the institutions where they have been implemented. Nonetheless, other instances of intramuscular vincristine injection are anticipated and should be rapidly recognized and quickly managed with local applications of cold and sodium bicarbonate.
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PMID:Accidental intramuscular vincristine: lack of untoward effects and recommendations for management. 1021 50

Recent studies have shown that angiogenesis, which is induced by VEGF, may be involved in the pathogenesis of hematopoietic malignancies. A human leukemia model consisting of T-lymphoblastic CEM/0, 7 monoclonal refractory clones resistant to both cytosine arabinoside (ara-C) and L-asparaginase (ASNase), Jurkat/E6-1 and U937, representing the leukemic blasts from relapsed patients with leukemias was investigated for secretion of VEGF before and after treatment with various agents. The T-lymphoblastic cell line, Jurkat/E6-1, was used as the negative control, which has been characterized as not expressing mRNA nor the VEGF protein, and did not secrete VEGF. With no treatment, U937, the positive control, secreted the highest VEGF concentration of 1612.7 pg/ml. The CEM/O wild type cell line and 5 other drug-resistant clones secreted VEGF at levels ranging from 180.9 to 414.2 pg/ml. Two CEM drug-resistant clones, CEM/ara-C/G/ASNase-0.5-1 and CEM/ara-C/G/ASNase-1-1, lacked VEGF production. Docetaxel (Taxotere, TXR), Vincristine (VCR), ASNase, and the Fit-1/Fc chimera, a specific inhibitor of VEGF-dependent human umbilical vein endothelial cell (HUVEC) proliferation, were tested for inhibition of VEGF secretion. Treatment of the leukemic cell lines with 2 microg/ml Flt-1/Fc chimera for 24 hours completely inhibited VEGF secretion to the detection limit of the assay (<10pg/ml). After 24 hours incubation with Flt-1/Fc chimera, the leukemic cells appeared to be undergoing apoptosis, based on microphotography examination, suggesting that VEGF could be used in an autocrine loop to promote cell survival by the leukemic cells. Treatment with 0.5, 1, and 2 microg/ml Flt-1/FC chimera for 48 hours demonstrated a 15-25% growth inhibition by MTT assay. Strong inhibition of VEGF secretion in the culture media was observed after 10 microM TXR or 0.1 microM VCR for 24 hours in the wild-type and drug-resistant clones, except CEM/ara-C/I, in comparison with controls. In contrast, treatment with 1 IU/ml ASNase, a specific T-cell protein inhibitor, in 5 cell lines for 24 hours demonstrated no inhibition of VEGF in CEM/0 3 drug-resistant clones and the myeloid U937 line. We conclude that the leukemia cell lines actively secrete VEGF, in vitro. TXR and VCR, but not ASNase, strongly inhibit the VEGF production, suggesting that inhibition of this growth factor may be a mechanism of antileukemic activity. Moreover, the leukemic cell lines examined here may constitute a useful model to study antiangiogenic drugs, alone or in combination with established drug regimens used against refractory leukemias.
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PMID:Taxotere and vincristine inhibit the secretion of the angiogenesis inducing vascular endothelial growth factor (VEGF) by wild-type and drug-resistant human leukemia T-cell lines. 1172 83


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