| Deamination of glutamine is a prerequisite for optimal asparagine deamination by asparaginases in vivo (CCG-1961). | |
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MedLine Citation:
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PMID: 15154634 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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BACKGROUND: Glutamine (Gln) deamination by asparaginase (ASNase) appears to contribute in the decrease of serum asparagine (Asn) levels and enhance leukemic cell apoptosis. The pharmacodynamic (PD) rationale is based on the role of Gln as the main amino group donor for Asn synthesis from aspartate by the enzyme asparagine synthetase (AS). MATERIALS AND METHODS: Relationships between ASNase enzymatic activity and Asn or Gln levels were examined in 274 pairs of pre- and post-ASNase serum specimens from 200 high-risk acute lymphoblastic leukemia (ALL) patients from the Children's Cancer Group (CCG-1961). Data were analyzed according to a novel PD model based on previous best-fit projections (NONMEM) from the CCG-1962 standard-risk ALL study. RESULTS: The PD results from high-risk and standard-risk ALL patients were superimposable. The percentages of Asn and Gln deamination were predicted by ASNase activity in patients' sera. Pharmacodynamic analyses strongly suggested that > 90% deamination of Gln must occur before optimal Asn deamination takes place in vivo. Asparaginase activity > or = 0.4 IU/ml yielded mean Gln and Asn % deamination values of 90%. Lower ASNase concentrations yielded lower Gln or Asn % deamination. This ASNase concentration coincides with the in vitro determined IC50 value on CEM/0 human T-lymphoblastic leukemia cells. CONCLUSION: Asparaginase activity of > or = 0.4 IU/ml provided optimal Asn and Gln deamination in high-risk ALL patients. Deamination of Gln correlates with enhanced serum Asn deamination in vivo. Therefore, deamination of Gln may enhance the antileukemic effect of ASNase. |
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Authors:
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Eduard H Panosyan; Rita S Grigoryan; Ioannis A Avramis; Nita L Seibel; Paul S Gaynon; Stuart E Siegel; Howard J Fingert; Vassilios I Avramis |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Anticancer research Volume: 24 ISSN: 0250-7005 ISO Abbreviation: Anticancer Res. Publication Date: 2004 Mar-Apr |
Date Detail:
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Created Date: 2004-05-24 Completed Date: 2004-06-24 Revised Date: 2007-11-15 |
Medline Journal Info:
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Nlm Unique ID: 8102988 Medline TA: Anticancer Res Country: Greece |
Other Details:
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Languages: eng Pagination: 1121-5 Citation Subset: IM |
Affiliation:
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Childrens Hospital Los Angeles, Los Angeles, CA 90027, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Antineoplastic Agents
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blood,
pharmacology* Asparaginase / blood, pharmacology* Asparagine / blood* Deamination Glutamine / blood* Humans Models, Biological Precursor Cell Lymphoblastic Leukemia-Lymphoma / blood*, drug therapy* Randomized Controlled Trials as Topic Risk Factors |
| Chemical | |
Reg. No./Substance:
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0/Antineoplastic Agents; 56-85-9/Glutamine; 7006-34-0/Asparagine; EC 3.5.1.1/Asparaginase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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