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

---

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

A 48-year-old man was referred to Sakai Municipal Hospital with nasal discharge and right facial swelling. The pathological findings of a nasal cavity tumor revealed stage IIB NK/T-cell lymphoma. He was admitted to our hospital and received CHOP therapy, resulting in progressive disease. Irradiation therapy combined with DeVIC chemotherapy also could not shrink his lymphoma. Then, two courses of L-asparaginase(L-Asp) were administered, resulting in partial improvement of the nasal and pharynx lesions, resolution of the fever and improvement of his performance status. On the day before a third course of L-Asp, he again developed a lowgrade fever. Although L-Asp was administered for several days, marked elevation of serum LDH, AST, ALT level, and thrombocytopenia persisted, and he died. Post-mortem examinations revealed hemophagocytosis in the bone marrow and liver, and infiltration of lymphoma cells into multiple organs including left lower lung, liver, spleen and kidneys. Although L-Asp was effective against nasal NK/T-cell lymphoma resistant to combination chemotherapy and irradiation therapy, the effectiveness of the single agent with L-Asp was only transient. L-Asp based regimen should be used as first-line therapy if asparagine synthetase protein expression is low using an immunohistochemical method.
...
PMID:[Temporary effective treatment with L-asparaginase for a patient with refractory nasal NK/T-cell lymphoma]. 1628 43

L-asparaginase is active in the treatment of acute lymphoblastic leukaemia (ALL) through the depletion of serum asparagine. Here we report that median asparagine synthetase (AS) mRNA levels were higher in acute myeloid leukaemia (AML) than ALL blasts in both children and adults, with intermediate levels in normal peripheral blood mononuclear cells (NPBMC). NPBMC versus child ALL (Tukeys multiple comparison test, P < 0.05); child ALL versus child AML (P < 0.001) and adult ALL versus adult AML (P < 0.01) were all significant and support the hypothesis that selectivity to treatment with l-asparaginase is due, at least in part, to lower AS expression.
...
PMID:Expression levels of asparagine synthetase in blasts from children and adults with acute lymphoblastic leukaemia. 1648 74

Chromosome rearrangement, a hallmark of cancer, has profound effects on carcinogenesis and tumor phenotype. We used a panel of 60 human cancer cell lines (the NCI-60) as a model system to identify relationships among DNA copy number, mRNA expression level, and drug sensitivity. For each of 64 cancer-relevant genes, we calculated all 4,096 possible Pearson's correlation coefficients relating DNA copy number (assessed by comparative genomic hybridization using bacterial artificial chromosome microarrays) and mRNA expression level (determined using both cDNA and Affymetrix oligonucleotide microarrays). The analysis identified an association of ERBB2 overexpression with 3p copy number, a finding supported by data from human tumors and a mouse model of ERBB2-induced carcinogenesis. When we examined the correlation between DNA copy number for all 353 unique loci on the bacterial artificial chromosome microarray and drug sensitivity for 118 drugs with putatively known mechanisms of action, we found a striking negative correlation (-0.983; 95% bootstrap confidence interval, -0.999 to -0.899) between activity of the enzyme drug L-asparaginase and DNA copy number of genes near asparagine synthetase in the ovarian cancer cells. Previous analysis of drug sensitivity and mRNA expression had suggested an inverse relationship between mRNA levels of asparagine synthetase and L-asparaginase sensitivity in the NCI-60. The concordance of pharmacogenomic findings at the DNA and mRNA levels strongly suggests further study of L-asparaginase for possible treatment of a low-synthetase subset of clinical ovarian cancers. The DNA copy number database presented here will enable other investigators to explore DNA transcript-drug relationships in their own domains of research focus.
...
PMID:Integrating data on DNA copy number with gene expression levels and drug sensitivities in the NCI-60 cell line panel. 1664 55

Modern clinical treatments of childhood acute lymphoblastic leukemia (ALL) employ enzyme-based methods for depletion of blood asparagine in combination with standard chemotherapeutic agents. Significant side effects can arise in these protocols and, in many cases, patients develop drug-resistant forms of the disease that may be correlated with up-regulation of the enzyme glutamine-dependent asparagine synthetase (ASNS). Though the precise molecular mechanisms that result in the appearance of drug resistance are the subject of active study, potent ASNS inhibitors may have clinical utility in treating asparaginase-resistant forms of childhood ALL. This review provides an overview of recent developments in our understanding of (a) the structure and catalytic mechanism of ASNS, and (b) the role that ASNS may play in the onset of drug-resistant childhood ALL. In addition, the first successful, mechanism-based efforts to prepare and characterize nanomolar ASNS inhibitors are discussed, together with the implications of these studies for future efforts to develop useful drugs.
...
PMID:Asparagine synthetase chemotherapy. 1675 5

L-asparaginase is important in the induction regimen for treating acute lymphoblastic leukemia. Cytotoxic complications are clinically significant problems lacking mechanistic insight. To reveal tissue-specific molecular responses to this drug, mice were administered asparaginase from either Escherichia coli (clinically used) or Wolinella succinogenes (novel, glutaminase-free form). Both enzymes abolished serum asparagine, but only the E. coli form reduced circulating glutamine. E. coli asparaginase reduced protein synthesis in liver and spleen but not pancreas via increased phosphorylation of the translation factor eIF2. In contrast, treatment with Wolinella caused no untoward changes in protein synthesis in any tissue examined. Treating mice deleted for the eIF2 kinase, GCN2, with the E. coli enzyme showed eIF2 phosphorylation to be GCN2-dependent, but only initially. Furthermore, although eIF2 phosphorylation was not increased in the pancreas or by Wolinella asparaginase, expression of the amino acid stress response genes, asparagine synthetase and CHOP/GADD153, increased as a result of both enzymes, even in tissues demonstrating no change in eIF2 phosphorylation. Finally, signaling downstream of the mammalian target of rapamycin kinase was repressed in liver and pancreas by E. coli but not Wolinella asparaginase. These data demonstrate that the nutrient stress response to asparaginase is tissue-specific and exacerbated by glutamine depletion. Importantly, increased expression of asparagine synthetase and CHOP does not require eIF2 phosphorylation, signifying alternate or auxiliary means of inducing gene expression under conditions of amino acid depletion in the whole animal.
...
PMID:Role of glutamine depletion in directing tissue-specific nutrient stress responses to L-asparaginase. 1693 16

During pine seed germination, a large amount of N mobilized from the storage proteins is re-allocated in the hypocotyl as free asparagine, as a result of the high levels of asparagine synthetase (AS) encoded by the PsAS1 gene. To determine the role of this re-allocated N reserve, a full-length cDNA encoding L: -asparaginase (ASPG) has been cloned from Scots pine (Pinus sylvestris L.) seedlings and characterized. Like other N-terminal nucleophile hydrolases, pine ASPG requires a post-translational processing to exhibit enzymatic activity. However, in contrast to previous reports on other plant ASPGs, purified recombinant pine ASPG does not undergo autoproteolytic cleavage in vitro. Our results suggest that the processing requires accessory proteins to assist in the proteolysis or in the proper folding before autocleavage in a divalent cation-dependent manner. Sequence comparison analysis revealed that the pine protein is included in the K+-dependent subfamily of plant ASPGs. The expression of the ASPG-encoding gene (PsASPG) was higher in organs with extensive secondary development of the vascular system. The increase in transcript abundance observed at advanced stages of hypocotyl development was concomitant with a decrease of PsAS1 transcript abundance and a remarkable increase in the number of xylem elements and highly lignified cell walls. These results, together with the precise localization of PsASPG transcripts in cells of the cambial region, suggest that the expression of PsAS1 and PsASPG is temporally coordinated, to control the re-allocation of N from seed storage proteins toward the hypocotyl to be later used during early development of secondary vascular system.
...
PMID:Coordination of PsAS1 and PsASPG expression controls timing of re-allocated N utilization in hypocotyls of pine seedlings. 1712 3

Drug resistance in lymphoblastic and myeloblastic leukemia cells is poorly understood, with several lines of evidence suggesting that resistance can be correlated with upregulation of human asparagine synthetase (hASNS) expression, although this hypothesis is controversial. New tools are needed to investigate this clinically important question, including potent hASNS inhibitors. In vitro experiments show an adenylated sulfoximine to be a slow-onset, tight-binding inhibitor of hASNS with nanomolar affinity. This binding affinity represents a 10-fold improvement over that reported for the only other well-characterized hASNS inhibitor. The adenylated sulfoximine has a cytostatic effect on L-asparaginase-resistant MOLT-4 cells cultured in the presence of L-asparaginase, an enzyme that depletes L-asparagine in the growth medium. These observations represent direct evidence that potent hASNS inhibitors may prove to be effective agents for the clinical treatment of acute lymphoblastic leukemia.
...
PMID:An inhibitor of human asparagine synthetase suppresses proliferation of an L-asparaginase-resistant leukemia cell line. 1718 29

Because of their low asparagine synthetase (ASNS) expression and asparagine biosynthesis, acute lymphoblastic leukemia (ALL) cells are exquisitely sensitive to asparagine depletion. Consequently, asparaginase is a major component of ALL therapy, but the mechanisms regulating the susceptibility of leukemic cells to this agent are unclear. In 288 children with ALL, cellular ASNS expression was more likely to be high in T-lineage ALL and low in B-lineage ALL with TEL-AML1 or hyperdiploidy. However, ASNS expression levels in bone marrow-derived mesenchymal cells (MSCs), which form the microenvironment where leukemic cells grow, were on average 20 times higher than those in ALL cells. MSCs protected ALL cells from asparaginase cytotoxicity in coculture experiments. This protective effect correlated with levels of ASNS expression: downregulation by RNA interference decreased the capacity of MSCs to protect ALL cells from asparaginase, whereas enforced ASNS expression conferred enhanced protection. Asparagine secretion by MSCs was directly related to their ASNS expression levels, suggesting a mechanism - increased concentrations of asparagine in the leukemic cell microenvironment - for the protective effects we observed. These results provide what we believe to be a new basis for understanding asparaginase resistance in ALL and indicate that MSC niches in the bone marrow can form a safe haven for leukemic cells.
...
PMID:Mesenchymal cells regulate the response of acute lymphoblastic leukemia cells to asparaginase. 1738 Feb 7

High expression of cellular asparagine synthetase (AS) is a causative factor for the resistance of leukemic cell to L-asparaginase therapy. This study was aimed to find single nucleotide polymorphism (SNPs) in the promotor region of asparagine synthetase (AS) gene and to determine if these SNPs have influence on the transcriptional activity of AS promotor. The DNA sequences of AS promoter (pAS) from 82 leukemic children and 45 controls were determined to screen for SNPs in this region and the AS mRNA level in these samples was quantified using real-time PCR assay. The results indicated that three SNPs were found in the sequenced pAS fragment. They were -239C/T, -92G/A and -62A/T respectively. The frequency of -92A allele was higher in leukemic samples than that in nonleukemic control (P<0.05). The gene expression level differed among the individuals with genotype of the -92G/A SNP, and the descending order was as follows: GA heterozygote > AA homozygote > GG homozygote. It is concluded that some features in leukemia might associate with SNP on -92A locus, and this SNP in pAS can be one of the factors influencing transcriptional activity of AS gene. The existence of the -92A allele variant contributes to a high expression of AS gene.
...
PMID:[Single nucleotide polymorphism in the promoter region of asparagine synthetase and its impact on the gene expression]. 1749 32

Acquired drug resistance eventually leads to treatment failure in T-cell acute lymphoblastic leukaemia (T-ALL). Immunophenotypic and cytogenetic heterogeneities within T-ALL influence susceptibility to cytotoxic therapy, and little is known about the mechanisms of drug resistance at specific stages of T-cell ontogeny. We developed tolerance to therapeutic concentrations of daunorubicin (DNR) and L-asparaginase (L-asp) in Jurkat (CD1a(-), sCD3(+)) and Sup T1 (CD1a(+), sCD3(-)) cell lines, having respective 'mature' and 'cortical' stages of developmental arrest. DNR resistant cells acquired multidrug resistance: 310-fold increased resistance to vincristine (VCR) and a 120-fold increased resistance to prednisolone (PRED). Microarray analysis identified upregulation of asparagine synthetase (ASNS) and argininosuccinate synthase 1 (ASS1) to cell lines with acquired resistance to L-asp, and in the case of DNR, upregulation of ATP-binding cassette B1 (ABCB1). Suppression of ABCB1, ASNS and ASS1 by RNA interference revealed their functional relevance to acquired drug resistance. Expression profiling of these genes in 80 T-ALL patients showed correlation with treatment response. This study expands the pool of available drug resistant cell lines having cortical and mature stages of developmental arrest, introduces three new drug resistant T-ALL cell lines, and identifies gene interactions leading to L-asp and DNR resistance.
...
PMID:Genetic alterations determine chemotherapy resistance in childhood T-ALL: modelling in stage-specific cell lines and correlation with diagnostic patient samples. 1785 4


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---