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| Primary information |
|---|
| ID | 11016 |
| Therapeutic ID | Th1241 |
| Protein Name | Asparaginase Escherichia coli |
| Sequence | >Th1241_Asparaginase_Escherichia_coli
MEFFKKTALAALVMGFSGAALALPNITILATGGTIAGGGDSATKSNYTVGKVGVENLVNAVPQLKDIANVKGEQVVNIGSQDMNDNVWLTLAKKINTDCDKTDGFVITHGTDTMEETAYFLDLTVKCDKPVVMVGAMRPSTSMSADGPFNLYNAVVTAADKASANRGVLVVMNDTVLDGRDVTKTNTTDVATFKSVNYGPLGYIHNGKIDYQRTPARKHTSDTPFDVSKLNELPKVGIVYNYANASDLPAKALVDAGYDGIVSAGVGNGNLYKSVFDTLATAAKTGTAVVRSSRVPTGATTQDAEVDDAKYGFVASGTLNPQKARVLLQLALTQTKDPQQIQQIFNQY
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| Molecular Weight | NA |
| Chemical Formula | C1377H2208N382O442S17 |
| Isoelectric Point | 4.67 |
| Hydrophobicity | 0.059 |
| Melting point | NA |
| Half-life | Plasma half life of L-asparagine derived from _E. coli_ following intravenous injection was 8-30 hrs [FDA Label]. Plasma half-life was 34 to 49 hours after intramuscular injection [FDA Label]. Half-life (mean ± SD) of native _E. coli_ asparaginase is approximately 1.28 ± 0.35 days [A31999]. |
| Description | Asparaginase derived from _Escherichia coli_ (L-asparagine amidohydrolase, EC 3.5.1.1) is an enzyme responsible for the metabolism of L-asparagine, by catalyzing L-asparagine into L-aspartic acid and ammonia. It also facilitates the production of oxaloacetate which is needed for general cellular metabolism. Asparaginase from _E. coli_ has clinically shown to exhibit antitumor actions in models of leukaemias [A31996, A31997]. L-asparaginase of _E. coli_ is marketed under several different trade names, including Elspar, for the treatment of acute lymphoblastic leukemia (ALL) as part of a multi-agent chemotherapeutic regimen. It is available as intramuscular or intravenous injections. Therapeutic L-asparaginase from _E. coli_ works by depleting the levels of non-essential amino acid, asparagine, in lymphoblastic leukemic cells thus promoting apoptotic cell death [A31999]. For patients who develop hypersensitivity to _E. coli_-derived formulations of L-asparaginase, the use of PEGylated or non-PEGylated [DB08886] is recommended [A31999]. |
| Indication/Disease | Indicated as a component of a multi-agent chemotherapeutic regimen for the treatment of patients with acute lymphoblastic leukemia (ALL) [FDA Label]. |
| Pharmacodynamics | In clinical trials of patients with previously untreated, standard-risk ALL, administration of asparaginase resulted in a decrease of plasma asparagine levels from average of 41 µM to less than 3 µM [FDA Label]. The native asparaginase in whom plasma enzyme activity before treatment was greater than 0.1 International Units/mL [FDA Label]. In this study, cerebrospinal fluid asparagine levels in patients treated with asparaginase decreased from 2.8 µM (pretreatment) to 1.0 µM and 0.3 µM at day 7 and day 28 of induction, respectively [FDA Label]. Native E. coli asparaginase results in asparagine depletion in 14 to 23 days following administration [A31999]. |
| Mechanism of Action | Asparagine is a non-essential amino acid that maintains DNA, RNA and protein synthesis and promotes cell growth. While healthy and normal cells are capable of obtaining asparagine via dietary intake or synthesizing the asparagine from aspartate via asparagine synthetase activity, lymphoblastic leukemic cells lack the asparagine synthetase enzyme and cannot produce asparagine _de novo_ [A31999]. Thus, leukemic cells rely on exogenous source of asparagine for protein synthesis and cell survival [A31999]. L-asparagine from E. coli serves to deplete plasma levels of asparagine in leukemic cells by converting L-asparagine to L-aspartic acid and ammonia [A31999], leading to reduced reduced DNA, RNA and protein synthesis; inhibition of cell growth; and ultimately the activation of apoptotic cell-death mechanisms [A31999]. Normal cells, however, are able to synthesize asparagine and thus are affected less by the rapid depletion produced by treatment with the enzyme asparaginase [FDA Label]. |
| Toxicity | No studies assessing the mutagenic or carcinogenic potential of _E. coli_ L-asparagine have been conducted. In the Ames assay, no mutagenic effect was demonstrated when tested against Salmonella typhimurium strains [FDA Label]. No studies have been performed on impairment of fertility [FDA Label]. Following a single, intravenous injection of 12,500 to 50,000 International Units L-asparagine/kg in rabbits, edema and necrosis of pancreatic islets were observed. The clinical relevance of this finding is unclear as it does not indicate pancreatitis [FDA Label]. |
| Metabolism | NA |
| Absorption | In a study in patients with metastatic cancer and leukemia, daily intravenous administration of L-asparaginase derived from _E. coli_ resulted in a cumulative increase in plasma levels. Following intramuscular injection in patients with metastatic cancer and leukemia, peak plasma levels of asparaginase was achieved 14 to 24 hours post-dosing [FDA Label]. Peak asparaginase activity of native _E. coli_ asparaginase can be observed in 24 to 48 hours following administration [A31999]. |
| Apparent volume of distribution was slightly greater than the plasma volume. Asparaginase levels in cerebrospinal fluid were less than 1% of concurrent plasma levels [A31999]. |
| Clearance | NA |
| Categories | Antineoplastic and Immunomodulating Agents |
| Patents Number | NA |
| Date of Issue | NA |
| Date of Expiry | NA |
| Drug Interaction | NA |
| Target | L-asparagine |
| Brand Name | Rylaze |
| Company | Jazz Pharmaceuticals, Inc. |
| Brand Description | Jazz Pharmaceuticals, Inc. |
| Prescribed For | Intramuscular |
| Chemical Name | 20 mg/1mL |
| Formulation | RYLAZE is contraindicated in patients with a history of: Serious hypersensitivity reactions to Erwinia asparaginase, including anaphylaxis Serious pancreatitis during previous asparaginase therapy Serious thrombosis during previous asparaginase therapy Serious hemorrhagic events during previous asparaginase therapy |
| Physical Appearance | abnormal liver test, nausea, musculoskeletal pain, fatigue, infection, headache, fever, drug hypersensitivity, febrile neutropenia, decreased appetite, sores or inflammation in the mouth, bleeding, high blood sugar (hyperglycemia), abdominal pain, fast heart rate, diarrhea, constipation, dehydration, numbness and tingling of extremities, cough, and insomnia. |
| Route of Administration | Rylaze is a cancer medicine. Erwinaze is used to treat acute lymphoblastic leukemia in adults and children at least 1 year old. Rylaze is used to treat lymphoblastic lymphoma in adults and children at least 1 month old who have become allergic to other forms of asparaginase such as Elspar or Oncaspar.... |
| Recommended Dosage | Rylaze (asparaginase erwinia chrysanthemi (recombinant) - rywn) is a prescription medicine used to treat the symptoms of Acute Lymphoblastic Leukemia, and Lymphoblastic Lymphoma. Rylaze may be used alone or with other medications. |
| Contraindication | NA |
| Side Effects | Asparaginase erwinia chrysanthemi (recombinant)-rywn contains an asparagine specific bacterial enzyme (L-asparaginase). L-asparaginase is a tetrameric enzyme that consists of four identical 35 kDa subunits with a combined molecular weight of 140 kDa. The amino acid sequence is identical to native asparaginase Erwinia chrystanthemi (also known as crisantaspase). The activity of asparaginase erwinia chrysanthemi (recombinant)-rywn is expressed in units, defined as the amount of enzyme that catalyzes the conversion of 1μmol of L-asparagine per reaction minute, per mg of protein. |
| Useful Link 1 | Link |
| Useful Link 2 | Link |
| Remarks | NA |