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)

Cell lines resistant to 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3- (2-chloroethyl)-3-nitrosourea hydrochloride (ACNU) show a high degree of collateral sensitivity to L-asparaginase. The mechanism for this phenomenon was investigated by comparing the nutritional requirements and asparagine synthetase activity of the resistant sublines to those of parent cells. Nine ACNU-resistant sublines were isolated from rat glioma 9L cells after incubation with various concentrations of ACNU in Ham's F-12 medium. The 9L cells grew independently of asparagine, developing well in asparagine-deficient Dulbecco's modified Eagle's medium. In contrast, the growth rates of all nine ACNU-resistant sublines decreased under the same conditions and required the addition of 10(-4) M asparagine for maximum growth. Asparagine synthetase activity in the ACNU-resistant cells was much lower than in the 9L cells, suggesting that the requirement for asparagine in the resistant sublines was due to reduced activity of this enzyme. A growth-inhibition assay showed that the ACNU-resistant sublines were more sensitive to L-asparaginase than 9L cells by up to 2 x 10(5)-fold. These results suggest that L-asparaginase therapy has the potential to become a new approach for treating acquired ACNU resistance.
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PMID:Hypersensitivity of rat glioma sublines with acquired ACNU resistance to L-asparaginase. 168 27

Three ACNU-resistant clones (R1, R3, and R12) were isolated from 9L rat glioma cells under selection pressure of ACNU in vitro. The authors have investigated the mechanisms of resistance and characteristics of these clones at the cellular level by studying cross-resistance patterns to chemical and physical agents. Although these resistant sublines showed complete cross-resistance to methyl-chloroethylnitrosourea (MCNU), no cross-resistance was observed for other alkylating agents, while each of the resistant sublines showed partial cross-resistance to structurally dissimilar toxic agents (vinblastine, Adriamycin, and VP-16). No difference in ACNU uptake was observed between 9L and R3 cells, and resistance patterns among alkylating agents suggested that the mechanism of ACNU resistance was specific to bifunctional nitrosoureas. Based on a transport study, this multidrug resistance could be explained by reduced intracellular uptake of these drugs, but there seemed little possibility that membrane P-glycoprotein, which usually is observed in typical multidrug-resistant cells, was expressed in these ACNU-resistant cells because enhanced drug efflux was not found in ACNU-resistant sublines. Significant collateral sensitivity to L-asparaginase indicated that ACNU might disturb the asparagine synthetic pathways by its mutagenic action. The increased level of total glutathione in the resistant sublines may be one mechanism of radiation or ACNU resistance.
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PMID:Cross-resistance patterns in ACNU-resistant glioma sublines in culture. 207 67

The human glioma-derived cell line D-54 MG and the human medulloblastoma-derived cell line TE-671 have been shown to be sensitive in culture to the pharmacological interference with glutamine metabolism by acivicin, 6-diazo-5-oxo-L-norleucine, and methionine sulfoximine. Using as a guide the multiple contributions of glutamine to the biosynthesis of proteins, purines, and pyrimidines, we now have identified six additional antimetabolites active against these lines in vitro at clinically relevant concentrations. The 50% growth-inhibitory levels of the drugs against D-54 MG in 6-day continuous exposure experiments were: L-asparaginase, 0.057 IU/ml; 5-fluorouracil, 0.5 micrograms/ml; 6-mercaptopurine, 0.8 micrograms/ml; actinomycin D, 0.0007 micrograms/ml; N-phosphonacetyl-L-aspartic acid, 2.3 micrograms/ml; and 5-azacytidine, 0.2 micrograms/ml (3-day exposure. The corresponding 50% growth-inhibitory values in TE-671 were: L-asparaginase, 0.54 IU/ml; 5-fluorouracil, 1.5 micrograms/ml; 6-mercaptopurine, 4.7 micrograms/ml; actinomycin D, 0.00044 micrograms/ml; N-phosphonacetyl-L-aspartic acid, 4.5 micrograms/ml; and 5-azacytidine, 0.49 micrograms/ml. Dipyridamole up to 10 micrograms/ml was inactive against both lines. The isobologram method was used to evaluate the effectiveness of several two-drug combinations which were biochemically designed. The sums of the optimal fractional inhibitory concentrations for the pairs were: acivicin plus L-asparaginase, 0.14; acivicin plus methionine sulfoximine, 0.40; 6-diazo-5-oxo-L-norleucine plus methionine sulfoximine, 0.60; acivicin plus 6-mercaptopurine, 1.0, all in TE-671; and acivicin plus 5-fluorouracil, 0.79, in D-54 MG. Our findings suggest that an antimetabolite regimen exploiting glutamine sensitivity might improve the chemotherapy of some human gliomas and medulloblastomas.
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PMID:Combination chemotherapy in vitro exploiting glutamine metabolism of human glioma and medulloblastoma. 402

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

Cancer cells display a variety of global metabolic changes, which aside from the glycolytic pathway largely involve amino acid metabolism. To ensure aggressive growth, tumor cells highly depend on amino acids, most notably due to their pivotal need of protein synthesis. In this study, we assessed the overall hypothesis that depletion of asparagine by E. coli-derived L-asparaginase might be a novel means for the therapy of one of the most recalcitrant neoplasms and for which no efficient treatment currently exists - glioblastoma (WHO grade IV). Our results suggest that certain glioma cell cultures are particularly susceptible to inhibition of proliferation by L-asparaginase, while others display a more resistant phenotype. In sensitive cells, L-asparaginase induces apoptosis with dissipation of mitochondrial membrane potential and activation of effector caspases. L-asparaginase-mediated apoptosis was accompanied by modulation of pro- and anti-apoptotic Bcl-2 family members, including Noxa, Mcl-1 and the deubiquitinase Usp9X. Given the impact of L-asparaginase on these molecules, we found that L-asparaginase potently overcomes resistance to both intrinsic apoptosis induced by the Bcl-2/Bcl-xL inhibitor, ABT263, and extrinsic apoptosis mediated by TRAIL even in glioma cells that are resistant towards L-asparaginase single treatment. RNA interference studies showed that Usp9X, Mcl-1, Noxa and Bax/Bak are involved in ABT263/L-asparaginase-mediated cell death. In vivo, combined treatment with ABT263 and L-asparaginase led to an enhanced reduction of tumor growth when compared to each reagent alone without induction of toxicity. These observations suggest that L-asparaginase might be useful for the treatment of malignant glial neoplasms.
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PMID:Metabolic reprogramming of glioblastoma cells by L-asparaginase sensitizes for apoptosis in vitro and in vivo. 2717 99