Use of ?-asparaginase in childhood ALL

Müller, Hans‐Joachim; Boos, Joachim

doi:10.1016/s1040-8428(98)00015-8

Cited by 420 publications

(336 citation statements)

References 110 publications

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“…Although the exact incidence of symptomatic hyperammonemia after asparaginase therapy is unknown, the small number of cases reported suggests a low frequency. Indeed, symptomatic hyperammonemia is not mentioned in recent overviews of toxicity of asparaginase treatment (Muller and Boos 1998;Earl 2009;Rytting 2010). In contrast, our observations suggest that symptomatic hyperammonemia is the rule rather than the exception after PEG-asparaginase administration.…”

Section: Resultsmentioning

confidence: 56%

“…Addition of asparaginase to treatment protocols has contributed significantly to this improved outcome (Muller and Boos 1998).…”

Section: Introductionmentioning

confidence: 99%

“…Despite its proven efficacy, several side effects of asparaginase treatment have been reported: hypersensitivity reactions, disturbed liver functions, coagulation disorders, pancreatitis, hyperlipidemia, and silent inactivation by antibodies (Muller and Boos 1998).…”

Section: Introductionmentioning

confidence: 99%

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High Incidence of Symptomatic Hyperammonemia in Children with Acute Lymphoblastic Leukemia Receiving Pegylated Asparaginase

et al. 2012

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Asparaginase is a mainstay of treatment of childhood acute lymphoblastic leukemia. Pegylation of asparaginase extends its biological half-life and has been introduced in the newest treatment protocols aiming to further increase treatment success. Hyperammonemia is a recognized side effect of asparaginase treatment, but little is known about its incidence and clinical relevance. Alerted by a patient with severe hyperammonemia after introduction of the new acute lymphoblastic leukemia protocol, we analyzed blood samples and clinical data of eight consecutive patients receiving pegylated asparaginase (PEG-asparaginase) during their treatment of acute lymphoblastic leukemia. All patients showed hyperammonemia (>50 mmol/L) and seven patients (88 %) showed ammonia concentrations > 100 mmol/L. Maximum ammonia concentrations ranged from 89 to 400 mmol/L. Symptoms varied from mild anorexia and nausea to headache, vomiting, dizziness, and lethargy and led to early interruption of PEG-asparaginase in three patients. No evidence of urea cycle malfunction was found, so overproduction of ammonia through hydrolysis of plasma asparagine and glutamine seems to be the main cause. Interestingly, ammonia concentrations correlated with triglyceride values (r ¼ 0.68, p < 0.0001), suggesting increased overall toxicity.The prolonged half-life of PEG-asparaginase may be responsible for the high incidence of hyperammonemia and warrants future studies to define optimal dosing schedules based on ammonia concentrations and individual asparagine and asparaginase measurements.

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Section: Resultsmentioning

confidence: 56%

“…Addition of asparaginase to treatment protocols has contributed significantly to this improved outcome (Muller and Boos 1998).…”

Section: Introductionmentioning

confidence: 99%

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High Incidence of Symptomatic Hyperammonemia in Children with Acute Lymphoblastic Leukemia Receiving Pegylated Asparaginase

et al. 2012

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“…The expression of asparaginase is a more specific therapy than nucleoside analogues, since acute lymphoblastic leukemia are asparagine auxotrophs and depend on the uptake of sufficient amounts of asparagine. Thus the expression of asparaginase depletes the availability of asparagine because it degrades it to aspartate [194]. The same concept of depletion applies to more recently found inhibitors of fatty acid synthase or choline kinase [198,199], which are in various (pre)clinical phases.…”

Section: Therapeutic Opportunities Of Cancer Metabolismmentioning

confidence: 98%

“…The concept of depletion has a long-standing history in cancer treatment with anti-folates, nucleoside analogues, and asparaginase [49,194,195] as examples. The underlying principle for the use of anti-folates and nucleoside analogues is the dependency of fast proliferating cells on de novo DNA synthesis.…”

Section: Therapeutic Opportunities Of Cancer Metabolismmentioning

confidence: 99%

Organ-Specific Cancer Metabolism and Its Potential for Therapy

Elia

Schmieder

Christen

et al. 2015

Handbook of Experimental Pharmacology

104

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KEYWORDS:Cancer metabolism, metabolic therapy, tissue specific metabolism, genetic drivers, epigenetic drivers, microenvironment, Warburg effect, reverse Warburg effect, mixed Warburg effect, triple-negative breast cancer, estrogen receptor positive breast cancer; prostate cancer, liver cancer, gluconeogenesis, fatty acid metabolism, glucose metabolism, glutamine metabolism, serine metabolism, metabolic normalization, metabolic depletion ABSTRACTTargeting the metabolism of cancer cells has the potential to lead to major advances in tumor therapy. Numerous promising metabolic drug targets have been identified. Yet, it has emerged that there is no singular metabolism that defines the oncogenic state of the cell. Rather, the metabolism of cancer cells is a function of the requirements of a tumor. Hence, the tissue of origin, the (epi)genetic drivers, aberrant signaling, and the microenvironment all together define these metabolic requirements. In this chapter we discuss in light of (epi)genetic, signaling, and environmental factors the diversity in cancer metabolism based on triple-negative and estrogen receptor positive breast cancer, early and late stage prostate cancer, and liver cancer. These types of cancer all display distinct and partially opposing metabolic behaviors (e.g. Warburg versus reverse Warburg metabolism). Yet, for each of the cancers their distinct metabolism supports the oncogenic phenotype. Finally, we will assess the therapeutic potential of metabolism based on the concepts of metabolic normalization and metabolic depletion.

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