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)

The cultured cell lines Yoshida ascites sarcoma, L-1210 mouse leukemia, OAT cell line derived from human lung cancer of the oat cell type, and P3HR-1 cell line derived from Burkitt's lymphoma have been used for the cell-killing kinetics study of anticancer agents and evaluation of the sensitivity of cells using the soft agar cloning assay method. It has been found that there are 2 types of actions: 1) Type I (cytocidal and concentration-dependent action). The dose survival curves of Type I agents fit the equation log S=log nminuskD (S, surviving fraction; D, concentration of agents; n and k are constant). The sensitivity of cells can be expressed by mean lethal dose 90% (MLD90=1/k). Four cell lines were compared on this basis, and some problems concerning the chemotherapy of human cancer are discussed. Alkylating agents and anticancer antibiotics belonged to this group.2) Type II (cytostatic and time-dependent action). The dose survival curves fit the Gompertz equation S=exp[(minusbeta/alpha)(1minus e-aD)] (beta, population reduction parameter; alpha, constant). The exposure survival curve is negative exponential, indicating that exposure time rather than concentration is the key fo effective cell killing of Type II agents. Difficulties in expression of sensitivity to Type II agents are discussed. Antimetabolites, Vinca alkaloids, and L-asparaginase belonged to this group. The cell-killing kinetics of anticancer agents and comparison of the sensitivity of cells may provide some indications not only of optimal dosage schedules but also of a new approach in screening systems for truly effective agents for human cancer.
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PMID:Cytocidal action of anticancer antigens: evaluation of the sensitivity of cultured animal and human cancer cells. 16 35

The N-[p-(fluorosulfonyl)benzyl] derivatives of L-asparagine and L-glutamine (1a,b) were synthesized as potential inhibitors of L-asparagine synthetase (ASase). Condensation of p-(fluorosulfonyl)benzylamine (2) with the suitably protected amino acid in the presence of dicyclohexylcarbodiimide, followed by deblocking, afforded 1a and 1b. Derivatives 1a and 1b at 10 mM inhibit ASase isolated from Novikoff hepatoma (rats) by 60 and 46%, respectively. Preliminary results on inhibition of Jensen sarcoma (L-asparaginase sensitive) and JA-1 sarcoma (L-asparaginase resistant) tissue cultures by 0.3 mM 1a (139,90%) and 1b (101, 103%), respectively, are discussed.
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PMID:Potential inhibitors of L-asparagine biosynthesis. 3. Aromatic sulfonyl fluoride analogs of L-asparagine and L-glutamine. 24 24

Combination effect of antitumor agents, including doxorubicin and daunorubicin, was evaluated on the concept of pharmacological synergism in ascites sarcoma-180 system. In alternate adminsitration, combinations of doxorubicin plus cyclophosphamide, thio-TEPA, carboquone, actinomycin-D, vinblastine, vincristine, methotrexate, cytarabine, 6-mercaptopurine, or L-asparaginase showed synergism, but in simultaneous one, only three agents, cyclophosphamide, carboquone, and cytarabine, were synergistic. On the other hand, combination of daunorubicin plus one of 8 agents (thio-TEPA, mitomycin-C, bleomycin, actinomycin-D, vinblastine, ancytabine, 6-mercaptopurine, and L-asparaginase) and 6 agents (cyclophosphamide, thio-TEPA, mitomycin-C, bleomycin, actinomycin-D, and vinblastine) provided synergism in alternate and simultaneous administration. Combination effect of agents was affected by the schedule of drug administration for doxorubicin, but weak for daunorubicin. Toxicity of doxorubicin or daunorubicin in combination with other drugs was also affected by the schedule of administration. Combination of a larger number of agents in simultaneous administration provided antagonism compared with an alternate administration.
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PMID:Interaction of antitumor agents including doxorubicin or daunorubicin in sarcoma-180 system. 61 16

The histidine ammonia-lyase from bacterial strain CAMR 5315 was partially purified to assess its effect on the growth of murine tumours. This strain was selected as the source after an extensive screening programme for histidine ammonia-lyases. The enzyme was partially purified by ammonium sulphate fractionation, chromatography on DEAE-cellulose and Sephadex G-150. The enzyme reduced circulating L-histidine levels in Wistar rats and in mice persisted with a half-life of 6-7 h. Neither LDH virus nor chemical modification with ethylacetimidate increased the half-life as observed with L-asparaginase and L-glutaminase. The enzyme was tested in mice against Ehrlich carcinoma, L5178Y lymphoblastic leukaemia, Mc/S sarcoma, B16 melanoma, P8157 mastocytoma, P1798 lymphosarcoma and the Gardner 6C3HED lymphosarcoma. The only tumours to show sensitivity to the enzyme were the Mc/S sarcoma against which a 65% increase in life span was observed at the highest enzyme dose, 1000 U/kg on alternate days over 14 days and the Ehrlich ascites carcinoma where cures were obtained at 250 U/kg on alternate days over 14 days, but only at inocula levels of 10(5) and 10(3) cells/animal respectively.
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PMID:The effect of histidine ammonia-lyase on some murine tumours. 688 63

It is established that the content of monoaminodicarboxylic acids and their amides in the organism tissues decreases not so sharply in the course of regressive development of the viral Moloney sarcoma as in case of its progressive growth. The process of the sarcoma spontaneous resolution is accompanied by a considerable increase in the content of these substances. Being used in the process of Moloney sarcoma growth and resolution, asparaginase, reducing the content of the above-mentioned substances in tissues, intensified in tumour growth and inhibited the tumour resolution. The contrary effect on the tumour growth was obtained by an additional introduction of monoaminodicarboxylic acids and their amides from outside. A conclusion is drawn about the influence of these substances metabolism on the formation of antitumoural defence physiological mechanisms, contributing in this case to a spontaneous tumour resolution.
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PMID:[Monoaminodicarboxylic acids and their amides in tissues during regressive tumor growth]. 705 57

Ten percent (214/2,059) of all dogs with cancer at North Carolina State University Veterinary Teaching Hospital had thrombocytopenia. The thrombocytopenia was associated with infectious/inflammatory etiologies in 4%, miscellaneous disorders (therapy, bone marrow failure, disseminated intravascular coagulation) in 35%, and neoplasia without identifiable secondary factors in 61% of cancer-bearing dogs. Classifying these dogs by tumor groups revealed the following proportionate ratios: lymphoid, 29%; carcinoma, 28%; sarcoma, 20%; hemic neoplasia, 7%; multiple, 5%; unclassified, 3%; benign, 3%; brain, 3%; and endocrine, 3%. Dogs with hemangiosarcoma, lymphoma, and melanoma were at increased risk of developing thrombocytopenia. Cytotoxic therapy was the major factor increasing the risk of thrombocytopenia in dogs with melanoma. Golden Retrievers were the only breed recognized with a predisposition to develop thrombocytopenia. If thrombocytopenia is identified in a dog with cancer, we recommend thorough evaluation of the coagulation system before surgery or therapy, and careful consideration of the risks and potential benefits of myelosuppressive or L-asparaginase therapy.
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PMID:Thrombocytopenia associated with neoplasia in dogs. 788 25

The resistance to L-asparaginase (ASNase) has been associated to the overexpression of asparagine synthetase (AS), although the role played by other metabolic adaptations has not been yet defined. Both in ASNase-sensitive Jensen rat sarcoma cells and in ARJ cells, their ASNase-resistant counterparts endowed with a five-fold increased AS activity, ASNase treatment rapidly depletes intracellular asparagine. Under these conditions, cell glutamine is also severely reduced and the activity of glutamine synthetase (GS) is very low. After 24 h of treatment, while sensitive cells have undergone massive apoptosis, ARJ cells exhibit a marked increase in GS activity, associated with overexpression of GS protein but not of GS mRNA, and a partial restoration of glutamine and asparagine. However, when ARJ cells are treated with both ASNase and L-methionine-sulfoximine (MSO), an inhibitor of GS, no restoration of cell amino acids occurs and the cell population undergoes a typical apoptosis. No toxicity is observed upon MSO treatment in the absence of ASNase. The effects of MSO are not referable to depletion of cell glutathione or inhibition of AS. These findings indicate that, in the presence of ASNase, the inhibition of GS triggers apoptosis. GS may thus constitute a target for the suppression of ASNase-resistant phenotypes.
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PMID:Inhibition of glutamine synthetase triggers apoptosis in asparaginase-resistant cells. 1603 93

Current therapies for sarcomas are often inadequate. This study sought to identify actionable gene targets by selective targeting of the molecular networks that support sarcoma cell proliferation. Silencing of asparagine synthetase (ASNS), an amidotransferase that converts aspartate into asparagine, produced the strongest inhibitory effect on sarcoma growth in a functional genomic screen of mouse sarcomas generated by oncogenic Kras and disruption of Cdkn2a. ASNS silencing in mouse and human sarcoma cell lines reduced the percentage of S phase cells and impeded new polypeptide synthesis. These effects of ASNS silencing were reversed by exogenous supplementation with asparagine. Also, asparagine depletion via the ASNS inhibitor amino sulfoximine 5 (AS5) or asparaginase inhibited mouse and human sarcoma growth in vitro, and genetic silencing of ASNS in mouse sarcoma cells combined with depletion of plasma asparagine inhibited tumor growth in vivo. Asparagine reliance of sarcoma cells may represent a metabolic vulnerability with potential anti-sarcoma therapeutic value.
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PMID:Functional genomic screening reveals asparagine dependence as a metabolic vulnerability in sarcoma. 2649 95