l-Asparaginase resistance in human leukemia—Asparagine synthetase

Haskell, Charles M.; Canellos, George P.

doi:10.1016/0006-2952(69)90375-x

Cited by 132 publications

(70 citation statements)

References 11 publications

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“…Leukemic lymphoblasts are exquisitely sensitive to the depletion of exogenous asparagine and glutamine because their capacity to produce their own asparagine supply is exceedingly low, owing to their generally low expression of the asparagine synthetase (ASNS) gene (1,14,15,(17)(18)(19)(20). In some experimental models of leukemia, cellular levels of ASNS were directly related to the resistance of leukemic cells to Asparaginase (17,19,20), suggesting that measurements of this enzyme in ALL cells from patients might be used as a predictor of leukemic cell sensitivity to asparaginase.…”

Section: Introductionmentioning

confidence: 99%

“…It had been suggested that upregulation of ASNS in leukemic cells upon exposure to asparaginase may be the leading mechanism of resistance to the drug (18), but Appel et al (23) recently found that upregulated ASNS expression did not correlate with a clinically poor response to the drug. Thus, the role of ASNS expression in leukemic cells with regard to asparaginase resistance may vary among genetic subtypes or, as suggested by others (24), it may have little or no relevance to drug sensitivity in vivo.…”

Section: Introductionmentioning

confidence: 99%

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Mesenchymal cells regulate the response of acute lymphoblastic leukemia cells to asparaginase

Iwamoto

Mihara²,

Downing³

et al. 2007

J. Clin. Invest.

306

255

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Mesenchymal cells regulate the response of acute lymphoblastic leukemia cells to asparaginase

Iwamoto

Mihara²,

Downing³

et al. 2007

J. Clin. Invest.

306

255

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“…[9][10][11][12][13][14] ALL cells are unable to produce asparagine, and are dependent on plasma levels of this amino acid for protein synthesis. [15][16] Plasma asparagine depletion results in inhibition of protein synthesis, which leads to inhibition of RNA and DNA synthesis with a subsequent apoptotic cell death of the leukemic cells. 1,2,17 The most commonly used form of asparaginase is the native (unmodified) enzyme derived from Escherichia coli.…”

Section: Introductionmentioning

confidence: 99%

Pharmacodynamics and safety of intravenous pegaspargase during remission induction in adults aged 55 years or younger with newly diagnosed acute lymphoblastic leukemia

Douer¹,

Yampolsky²,

Cohen³

et al. 2006

Blood

149

106

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In contrast to that in children, pharmacokinetic, pharmacodynamic, and safety information on pegaspargase in adults is very limited. We administered a single intravenous dose of pegaspargase (2000 IU/m 2 ) as part of a standard frontline induction regimen to 25 adults with newly diagnosed acute lymphoblastic leukemia (ALL), and obtained serum samples on several time points. The population mean peak serum concentration of asparaginase enzymatic activity was 1 IU/mL, the elimination half-life was 7 days, and the

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“…Normal cells can synthesize asparagine as needed; however, asparagine synthetase activity in some malignant lymphoblasts is low, and thus endogenous production of this amino acid is diminished. 1,2 Asparaginase hydrolyzes asparagine to aspartic acid and ammonia extracellularly, depriving neoplastic cells of their normal source of asparagine. Asparagine-dependent protein synthesis is halted with subsequent inhibition of nucleic acid synthesis, which decreases leukemic cell proliferation.…”

Section: Introductionmentioning

confidence: 99%

Anti-asparaginase antibodies following E. coli asparaginase therapy in pediatric acute lymphoblastic leukemia

et al. 1998

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Asparaginase is an effective antileukemic agent and is included in most front-line protocols for pediatric acute lymphoblastic leukemia (ALL) worldwide; however, allergic reactions to asparaginase may be dose-limiting. We evaluated plasma anti-asparaginase antibody concentrations in a cohort of children with newly diagnosed ALL, who did and who did not exhibit clinical hypersensitivity, after Escherichia coli (E. coli) asparaginase therapy. Thirty-five children who received asparaginase 10 000 IU/m 2 i.m. three times weekly for nine doses as part of both multiagent induction and reinduction chemotherapy, and seven monthly doses during the first 7 months of continuation treatment, were studied. Twenty-two patients experienced initial allergic reactions to asparaginase during continuation (n = 20) or reinduction (n = 2) phases and 13 children did not exhibit any reaction. An enzyme-linked immunosorbent assay (ELISA) was used to measure anti-asparaginase antibodies in plasma samples, diluted 1:3200, using E. coli asparaginase as the antigen. The median anti-asparaginase antibody concentration (OD at 1:3200 dilution) increased from 0.039 at induction to 0.506 at reinduction in patients who exhibited clinical hypersensitivity (P = 0.0002). By comparison, median antibody level increased from 0.011 to 0.032 OD at identical time points in patients who did not react to asparaginase (P = 0.02). Both post-induction and post-reinduction anti-asparaginase antibody levels were higher in reacting than in nonreacting patients (P = 0.004 and P = 0.01, respectively). Antibody levels were inversely related to the time elapsed between the reaction and sampling (P = 0.011). Although anti-asparaginase antibody levels increased from the post-induction plasma sample to the post-reinduction sample in 28 of 35 patients regardless of whether they exhibited clinical hypersensitivity, patients with hypersensitivity reactions had higher antibody levels than did identically treated control patients at comparable time points in therapy. Therefore, antibody analysis may be of clinical value in predicting future hypersensitivity.

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l-Asparaginase resistance in human leukemia—Asparagine synthetase

Cited by 132 publications

References 11 publications

Mesenchymal cells regulate the response of acute lymphoblastic leukemia cells to asparaginase

Mesenchymal cells regulate the response of acute lymphoblastic leukemia cells to asparaginase

Pharmacodynamics and safety of intravenous pegaspargase during remission induction in adults aged 55 years or younger with newly diagnosed acute lymphoblastic leukemia

Anti-asparaginase antibodies following E. coli asparaginase therapy in pediatric acute lymphoblastic leukemia

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