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)

The role of high-dose etoposide in the initial treatment of newly diagnosed adult ALL was assessed in a combined clinical and laboratory study. Therapy on protocol JH8802 consisted of two induction modules, module 1 containing prednisone, vincristine, high-dose etoposide and L-asparaginase (L-asp), followed by module 2 containing cytarabine (Ara-C) and daunorubicin (DNR). Patients achieving a complete remission (CR) underwent bone marrow transplantation (BMT) or intensive maintenance therapy. Results were compared to the preceding protocol (JH8302), which was similar except for omission of etoposide and L-asp. The CR rate following module 1 was 45% on protocol JH8802 and 9% on protocol JH8302 (p < 0.0002). Nonetheless, the two protocols had similar CR rates following module 2 (69% on protocol JH8302; 77% on JH8802) and indistinguishable survivals. Laboratory investigations performed on blasts harvested prior to chemotherapy revealed two factors that could potentially contribute to decreased etoposide sensitivity in ALL blasts. A flow microfluorimetry-based assay of nuclear DNR accumulation detected small P-glycoprotein (Pgp)-mediated decreases in drug accumulation in a quarter of the samples. Western blotting demonstrated that topoisomerase II was present in all samples but was diminished in amount compared to the Molt3 human ALL cell line. Immunoperoxidase staining with affinity-purified antibodies revealed that topo II alpha, the target for etoposide, was detectable in only a minority of the blasts (median 7.5%, range < 1-35%) at diagnosis. These observations raise the possibility that alterations in drug accumulation and diminished target enzyme levels might both limit the long-term efficacy of a single course of high dose etoposide administered early in the treatment of adult ALL.
Leuk Lymphoma 1996 Sep
PMID:Addition of etoposide to initial therapy of adult acute lymphoblastic leukemia: a combined clinical and laboratory study. 902 88

Helicobacter pylori can utilise amino acids as the sole carbon energy source. The present study demonstrated that H. pylori grown in continuous culture in a defined medium containing glucose and amino acids utilised alanine, arginine, asparagine, aspartate, glutamine, glutamate, proline and serine. Specific asparaginase and glutaminase enzymes deaminated asparagine and glutamine respectively to aspartate and glutamate, with the production of ammonia. The glutaminase activity was inhibited by 6-diazo-5-oxo-L-norleucine. All the 13 strains of H. pylori tested produced both glutaminase and asparaginase activities. Glutamine is important in the health of the gastric and intestinal mucosa and is a primary energy source for lymphocytes. Depletion of glutamine at the site of H. pylori infection may be of significance in the pathogenesis of H. pylori-associated diseases such as peptic ulcer and gastric cancer.
J Med Microbiol 1997 Sep
PMID:Amino acid utilisation and deamination of glutamine and asparagine by Helicobacter pylori. 929 92

The ndh gene of Escherichia coli encodes the non-proton-translocating NADH dehydrogenase II. Expression of the ndh gene is subject to a complex network of regulatory controls at the transcriptional level. Under anaerobic conditions ndh is repressed by the regulator of fumarate and nitrate reduction (FNR). However, in the absence of FNR, ndh expression is activated by the amino acid response regulator (Arr) during anaerobic growth in rich medium. Expression of the ndh gene varies during the growth cycle in response to the intracellular concentration of the heat-stable DNA-binding protein, Fis. In this work two additional heat-stable proteins, integration host factor (IHF) and the histone-like protein HU were found to interact with the ndh promoter. IHF was shown to bind at three sites centred at +26, -17 and -58 in the ndh promoter (Kd = 10(-8) M), to prevent open-complex formation and to repress ndh transcription in vitro. Studies with an ndh-lacZ fusion confirmed that IHF represses ndh expression in vivo. Two putative binding sites for Arr, which overlap the two FNR boxes in the ndh promoter, were identified. Studies with the FNR-activated and amino-acid-inducible asparaginase II gene (ansB) showed that IHF and a component of the Arr-containing fraction (but not HU) interact with the corresponding ansB promoter.
Microbiology (Reading) 1997 Sep
PMID:Regulation of the ndh gene of Escherichia coli by integration host factor and a novel regulator, Arr. 930 70

L-Asparaginase is the major induction-phase agent for treatment of acute lymphoblastic leukemia (ALL) and an important adjuvant in treatment of non-Hodgkin's lymphoma (NHL). However, L-asparaginase-induced disturbances of clotting homeostasis may result in thrombosis or hemorrhage. Thrombotic occlusion of small cerebral veins has been reported in patients with ALL treated with this agent, but have not been described in NHL patients or those treated with the long-acting synthetic congener, pegaspargase. We report a 16-year-old boy with NHL who developed a focal motor seizure 15 min after receiving intravenous pegaspargase. MRI of the brain demonstrated multiple cortical and subcortical lesions that most likely represented focal brain edema due to thrombotic venous occlusion, which improved remarkably within 3 days and completely resolved within 3 weeks without specific intervention or permanent clinical consequences. This process must be considered when such changes are detected in NHL patients.
Pediatr Neurol 1997 Sep
PMID:Reversible MRI lesions due to pegaspargase treatment of non-Hodgkin's lymphoma. 936 5

It is well established that in acute lymphoblastic leukemia (ALL) patients L-asparaginase (L-Ase) provokes thrombotic events reducing coagulation inhibitors in both adults and children. A tight correlation between thrombotic and hemorrhagic complications and ALL has also been hypothesized because of the high incidence of disseminated intravascular coagulation (DIC) found during the early period of chemotherapeutic treatment apart from L-Ase. All the authors reporting on this subject, however, consider the remission induction phase of treatment the most risky, if not exclusive, for the development of a thrombotic event, in particular if it includes the administration of L-Ase. We report here two cases of ALL patients who experienced a cerebral sinus thrombosis in a later phase of treatment, demonstrating that the thrombotic risk is surely exacerbated by chemotherapy but is not exclusive to the remission induction period.
Ann Hematol 1997 Sep
PMID:Thrombotic events are not exclusive to the remission induction period in patients with acute lymphoblastic leukemia: a report of two cases of cerebral sinus thrombosis. 936 81

We have compared the antileukemic activity of the investigational biotherapeutic agent B43-PAP to the antileukemic activities of the standard chemotherapeutic drugs vincristine (VCR), methylprednisolone (PDN), L-asparaginase (L-ASP) as single agents as well as in a 3-drug combination regimen ("VPL") using a SCID mouse model of human B-cell precursor (BCP) acute lymphoblastic leukemia (ALL). When mice (N = 95) were challenged with 1 x 10(6) NALM-6 leukemia cells, all of them died of disseminated leukemia with a median event-free survival (EFS) of 47 +/- 6 days. B43-PAP was more active than VCR, PDN, or L-ASP and the two-drug combinations VCR + B43-PAP, PDN + B43-PAP, or L-ASP + B43-PAP were not significantly more active than B43-PAP. The 120 days EFS outcome results were 46 +/- 13% for B43-PAP (Median EFS = 92 +/- 22 days), 0 +/- 0% for VCR (Median EFS = 49 +/- 1 days), 40 +/- 22% for PDN (Median EFS = 100 +/- 20 days), 0 +/- 0% for L-ASP (Median EFS = 41 +/- 1 days), 60 +/- 22% for VCR + B43-PAP (Median EFS = >120 days), 60 +/- 22% for PDN + B43-PAP (Median EFS = >120 days), and 50 +/- 25% for L-ASP + B43-PAP (Median EFS = 93 +/- 27 days), When mice (N = 61) were challenged with 5 x 10(6) NALM-6 cells, all of them rapidly died of disseminated leukemia with a median EFS of 37 +/- 3 days. The 3-drug combination "VPL" (Median EFS = 75 +/- 23 days) was slightly less active than B43-PAP (Median EFS = 84 +/- 19 days) (P = 0.09). Notably, the combination of "VPL" with B43-PAP (i.e., VPLB) resulted in 100% survival. By comparison, the combination of "VPL" with daunorubicin (i.e., VPLD) (Median EFS = 69 +/- 31 days) was not more active than VPL. To our knowledge, this preclinical study is the first to demonstrate the feasibility and superb antileukemic activity of immunochemotherapy using anti-CD19 immunotoxin in combination with the standard 3-drug combination "VPL" against BCP ALL.
Leuk Lymphoma 1998 Sep
PMID:Treatment of human B-cell precursor leukemia in SCID mice by using a combination of the anti-CD19 immunotoxin B43-PAP with the standard chemotherapeutic drugs vincristine, methylprednisolone, and L-asparaginase. 972 Jul 24

We describe two cases of drug-induced hypertriglyceridemia, one associated with interferon alfa-2b and the other with asparaginase, each of which is mediated through a different mechanism. Hypertriglyceridemia caused by these medications is not listed as an adverse reaction in the Physicians' Desk Reference, one of the most popular pharmacologic reference sources used in the United States. We emphasize the importance of early recognition of this metabolic effect and the potential life-threatening complication, acute pancreatitis.
South Med J 1999 Sep
PMID:Drug-induced hypertriglyceridemia with and without pancreatitis. 1049 70

A gene (ansB) encoding a class II glutaminase/asparaginase has been cloned from Pseudomonas fluorescens and characterized by DNA sequencing, promoter analysis and heterologous expression in Escherichia coli. We show that ansB is monocistronic and depends on the alternate sigma factor sigma 54 for expression. A second open reading frame located downstream of ansB is highly homologous to a number of bacterial genes that encode secreted endonucleases of unknown function.
FEMS Microbiol Lett 1999 Sep 15
PMID:Cloning, sequence analysis, and expression of ansB from Pseudomonas fluorescens, encoding periplasmic glutaminase/asparaginase. 1049 83

The nematode cuticle is a complex extracellular structure which is secreted by an underlying syncytium of hypodermal cells. Recent studies have demonstrated that the cuticle of parasitic nematodes is a dynamic structure with important absorptive, secretory, and enzymatic activities. In addition, the cuticle serves as a protective barrier against the host. A 48-h third stage larval Dirofilaria immitis cDNA library was immunoscreened with sera raised against larval cuticles. One clone, L3MC4 that reacted strongly with the anti-cuticle antisera was sequenced. The composite cDNA sequence comprises 2073 bp coding for a full-length protein of 590 amino acids. GenBank analysis showed that DiAsp had significant similarity to a Caenorhabditis elegans gene-product (54% identity) and to other asparaginases at the amino acid level. Escherichia coli-expressed recombinant DiAsp (rDiAsp) catalysed the hydrolysis of asparagine to aspartate and ammonia. Antibodies raised against D. immitis larval cuticles reacted with rDiAsp in immunoblots. This is the first report of identification of a cDNA clone encoding an asparaginase enzyme from a parasitic nematode.
Int J Parasitol 1999 Sep
PMID:Identification of an asparagine amidohydrolase from the filarial parasite Dirofilaria immitis. 1057 32

The relapse rate in childhood acute lymphoblastic leukemia (ALL) is approximately 30% but few reinduction regimens have investigated the intensive use of polyethylene glycol Escherichia coli asparaginase (PEG-Asp). Therefore, we assessed the pharmocokinetics and efficacy of PEG-Asp in this setting. Children with B-precursor ALL, in first marrow and/or extramedullary relapse were eligible. Reinduction included doxorubicin on day 1, prednisone for 28 days, vincristine weekly for 4 weeks, and PEG-Asp either weekly or biweekly by randomization. Asparaginase levels and antibody to both E coli asparaginase and PEG-asp were measured weekly just before each PEG-asp dose. Overall, 129 of 144 patients (pts) (90%) achieved a complete remission (CR). There was a highly significant difference in CR rates between weekly (69 of 71; 97%) and biweekly (60 of 73; 82%) PEG-Asp dosing (P =.003). Grade 3 or 4 infectious toxicity was common (50%), but only 4 pts died of sepsis during induction. Other toxicities were infrequent and hypersensitivity was rare (6 of 144; 4%). Low asparaginase levels were associated with high antibody titers to either native (P =.024) or PEG asp (P =.0013). The CR rate was significantly associated with higher levels of asparaginase (P =. 012). Patients with ALL in first relapse receiving weekly PEG-Asp had a higher rate of second remission compared with biweekly dosing. Low levels of asparaginase were associated with high antibody titers. Increased asparaginase levels may correlate with an improved CR rate. The use of intensive PEG-Asp should be explored further in the treatment of ALL. (Blood. 2000;96:1709-1715)
Blood 2000 Sep 01
PMID:Weekly polyethylene glycol conjugated L-asparaginase compared with biweekly dosing produces superior induction remission rates in childhood relapsed acute lymphoblastic leukemia: a Pediatric Oncology Group Study. 1096 68


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