l-Asparagine depletion levels and l-asparaginase activity in plasma of children with acute lymphoblastic leukemia under asparaginase treatment

Tsurusawa, Masahito; Chin, Motoaki; Iwai, Asayuki; Nomura, Keiko; Maeba, Hideaki; Taga, Takashi; Higa, Takeshi; Kuno, Tomoko; Hori, Toshinori; Muto, Akiko; Yamagata, Miyo

doi:10.1007/s00280-003-0734-5

Cited by 26 publications

(15 citation statements)

References 14 publications

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“…Asparaginase-induced depletion of circulating asparagine and glutamine might ultimately induce cell death by affecting both tumor energy metabolism and macromolecular biosynthesis[16,19]. We found that asparagine was entirely depleted in both BM and PB from day 8 to the end of induction therapy, consistent with previous reports[53,54]. In contrast, glutamine levels in PB were depleted during the first week of treatment, but recovered considerably by the end of therapy.…”

Section: Discussionsupporting

confidence: 91%

Metabolomics of the Tumor Microenvironment in Pediatric Acute Lymphoblastic Leukemia

et al. 2013

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The tumor microenvironment is emerging as an important therapeutic target. Most studies, however, are focused on the protein components, and relatively little is known of how the microenvironmental metabolome might influence tumor survival. In this study, we examined the metabolic profiles of paired bone marrow (BM) and peripheral blood (PB) samples from 10 children with acute lymphoblastic leukemia (ALL). BM and PB samples from the same patient were collected at the time of diagnosis and after 29 days of induction therapy, at which point all patients were in remission. We employed two analytical platforms, high-resolution magnetic resonance spectroscopy and gas chromatography-mass spectrometry, to identify and quantify 102 metabolites in the BM and PB. Standard ALL therapy, which includes l-asparaginase, completely removed circulating asparagine, but not glutamine. Statistical analyses of metabolite correlations and network reconstructions showed that the untreated BM microenvironment was characterized by a significant network-level signature: a cluster of highly correlated lipids and metabolites involved in lipid metabolism (p<0.006). In contrast, the strongest correlations in the BM upon remission were observed among amino acid metabolites and derivatives (p<9.2×10-10). This study provides evidence that metabolic characterization of the cancer niche could generate new hypotheses for the development of cancer therapies.

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Section: Discussionsupporting

confidence: 91%

Metabolomics of the Tumor Microenvironment in Pediatric Acute Lymphoblastic Leukemia

et al. 2013

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“…Different from normal cells, ALL cells are unable to synthesize the non-essential amino acid asparagine (46); thus, the survival of leukemic cells depends on circulating asparagine. This forms the basis of using E. coli asparaginase in the clinical treatment of ALL (46–47), where the enzyme catalyzes the decomposition of L-asparagine to L-aspartic acid and ammonia. In current protocols of ALL treatment, asparaginase, along with other drugs, are often used in the remission-induction phase, whereas methotrexate plus mercaptopurine are frequently used in consolidation treatment (48).…”

Section: Discussionmentioning

confidence: 99%

6-Thioguanine Reactivates Epigenetically Silenced Genes in Acute Lymphoblastic Leukemia Cells by Facilitating Proteasome-mediated Degradation of DNMT1

et al. 2011

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Thiopurines including 6-thioguanine ( S G), 6-mercaptopurine, and azathioprine are effective anticancer agents with remarkable success in clinical practice, especially in effective treatment of acute lymphoblastic leukemia (ALL). S G is understood to act as a DNA hypomethylating agent in ALL cells, however, the underlying mechanism leading to global cytosine demethylation remains unclear. Here we report that S G treatment results in reactivation of epigenetically silenced genes in T leukemia cells. Bisulfite genomic sequencing revealed that S G treatment universally elicited demethylation in the promoters and/or first exons of the genes that were reactivated. S G treatment also attenuated the expression of histone lysine-specific demethylase 1 (LSD1), thereby stimulating lysine methylation of the DNA methylase DNMT1 and triggering its degradation via the ubiquitin-proteasomal pathway. Taken together, our findings reveal a previously uncharacterized but vital mechanistic link between S G treatment and DNA hypomethylation. Cancer Res; 71(5); 1904-11. Ó2011 AACR.

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“…In our previous Dutch Childhood Oncology Group (DCOG) ALL‐10 protocol, patients were treated with a fixed dose of 2,500 IU/m 2 PEGasparaginase . These patients had relatively high asparaginase activity levels (mean 899 IU/L), possibly causing unnecessary toxicity since an asparaginase activity level of >100 IU/l is considered sufficient for complete asparagine depletion . In addition, 8% of the patients turned out to have silent inactivation .…”

Section: Introductionmentioning

confidence: 99%

A cost analysis of individualized asparaginase treatment in pediatric acute lymphoblastic leukemia

Kloos

Groot

Litsenburg

et al. 2017

Pediatric Blood & Cancer

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l-Asparagine depletion levels and l-asparaginase activity in plasma of children with acute lymphoblastic leukemia under asparaginase treatment

Abstract: These results show that Asn levels are strongly correlated with plasma ASNase activity even at low enzyme activities (<50 U/l) and that this sensitive ASNase assay can be used to estimate plasma Asn depletion levels.

Cited by 26 publications

References 14 publications

Metabolomics of the Tumor Microenvironment in Pediatric Acute Lymphoblastic Leukemia

Metabolomics of the Tumor Microenvironment in Pediatric Acute Lymphoblastic Leukemia

6-Thioguanine Reactivates Epigenetically Silenced Genes in Acute Lymphoblastic Leukemia Cells by Facilitating Proteasome-mediated Degradation of DNMT1

A cost analysis of individualized asparaginase treatment in pediatric acute lymphoblastic leukemia

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