Pharmacodynamic effects in the cerebrospinal fluid of rats after intravenous administration of different asparaginase formulations

Ballerini, Andrea; Moro, Federico; Nerini, Ilaria Fuso; Marzo, C; Clemente, Angelo Di; Ferrari, Mariella; D’Incalci, Maurizio; Biondi, Andrea; Colombini, Antonella; Conter, Valentino; Porcu, Luca; Cervo, Luigi; Rizzari, Carmelo; Zucchetti, Massimo

doi:10.1007/s00280-017-3307-8

Cited by 5 publications

(10 citation statements)

References 12 publications

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“…11 Conversely, this may not be possible for PEG-asparaginase, mainly because of its tertiary structure. 16,32,33 However, so far there is no clear proof that any asparaginase product determines any degree of CSF asparagine depletion in humans by directly penetrating the CSF. To contribute to this issue a preclinical study was recently conducted to evaluate whether the three commercially available asparaginase formulations have different abilities to enter the CSF and reduce local asparagine levels.…”

Section: Discussionmentioning

confidence: 99%

“…Even with the limitations of the model used in that preclinical experience, the enzymatic activity measured in CSF demonstrated that asparaginase products, in particular both the native forms derived from Erwinia chrysanthemi and E. coli , may transiently penetrate the CNS when administered at high doses, whereas the PEG-asparaginase product does not, most probably because of the differences in molecular weight. 16,34,35…”

Section: Discussionmentioning

confidence: 99%

“…4,13–15 We very recently demonstrated, even with the limitations of the experimental preclinical model adopted, that in the CSF of rats asparaginase activity levels could be measured, consistently even if transiently, only for non-pegylated formulations. 16…”

Section: Introductionmentioning

confidence: 99%

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Asparagine levels in the cerebrospinal fluid of children with acute lymphoblastic leukemia treated with pegylated-asparaginase in the induction phase of the AIEOP-BFM ALL 2009 study

et al. 2019

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Asparagine levels in cerebrospinal fluid and serum asparaginase activity were monitored in children with acute lymphoblastic leukemia treated with pegylated-asparaginase. The drug was given intravenously at a dose of 2,500 IU/m 2 on days 12 and 26. Serum and cerebrospinal fluid samples obtained on days 33 and 45 were analyzed centrally. Since physiological levels of asparagine in the cerebrospinal fluid of children and adolescents are 4-10 μmol/L, in this study asparagine depletion was considered complete when the concentration of asparagine was ≤0.2 μmol/L, i.e. below the lower limit of quantification of the assay used. Over 24 months 736 patients (AIEOP n=245, BFM n=491) and 903 cerebrospinal fluid samples (n=686 on day 33 and n=217 on day 45) were available for analysis. Data were analyzed separately for the AIEOP and BFM cohorts and yielded superimposable results. Independently of serum asparaginase activity levels, cerebrospinal fluid asparagine levels were significantly reduced during the investigated study phase but only 28% of analyzed samples showed complete asparagine depletion while relevant levels, ≥1 μmol/L, were still detectable in around 23% of them. Complete cerebrospinal fluid asparagine depletion was found in around 5-6% and 33-37% of samples at serum asparaginase activity levels <100 and ≥ 1,500 IU/L, respectively. In this study cerebrospinal fluid asparagine levels were reduced during pegylated-asparaginase treatment, but complete depletion was only observed in a minority of patients. No clear threshold of serum pegylated-asparaginase activity level resulting in complete cerebrospinal fluid asparagine depletion was identified. The consistency of the results found in the two independent data sets strengthen the observations of this study. Details of the treatment are available in the European Clinical Trials Database at https://www.clin-icaltrialsregister.eu/ctr-search/trial/2007-004270-43/IT .

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Asparagine levels in the cerebrospinal fluid of children with acute lymphoblastic leukemia treated with pegylated-asparaginase in the induction phase of the AIEOP-BFM ALL 2009 study

et al. 2019

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“…11,14,16 Native E. coli and Erwinia asparaginase can penetrate the CSF in small amounts, whereas the larger PEGasparaginase cannot. 18,19,25,27 Our finding that traumatic lumbar punctures (≥1000 erythrocytes/μl) did result in lower L-asparagine levels supports the theory that small amounts of asparaginase in the CSF are needed to accomplish complete CSF L-asparagine depletion.…”

Section: Discussionmentioning

confidence: 56%

Depletion of d‐ and l‐asparagine in cerebrospinal fluid in acute lymphoblastic leukemia during PEGasparaginase therapy

Brigitha

Pieters

Struys

et al. 2022

Pediatric Blood & Cancer

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Background l‐Asparaginase hydrolyzes l‐asparagine and not its enantiomer d‐asparagine. Unlike l‐asparagine, d‐asparagine is nonessential for the survival of acute lymphoblastic leukemia (ALL) cells. Studies showed that serum asparagine is depleted below 0.5 μM in ≥96% of the patients during pegylated Escherichia coli l‐asparaginase (PEGasparaginase) treatment; however, cerebrospinal fluid (CSF) asparagine levels are depleted in only 20%–30% of the patients. Thus far, studies only reported the total CSF asparagine (sum of d‐ and l‐asparagine) concentrations. Data on the pharmacological goal, which is l‐asparagine depletion, are lacking. Method Therefore, we studied this in 30 patients (95 samples) with newly diagnosed ALL. They received two doses of PEGasparaginase on day 4 and 18 in induction. Results Median age at diagnosis was 5.7 years (range 1.5–17.1 years). d‐Asparagine and l‐asparagine concentrations (median (range)) before PEGasparaginase treatment were 0.038 (0.0–0.103) μM and 6.1 (1.82–11.5) μM, respectively. CSF l‐asparagine concentrations were reduced by 85% (76%–100%) and approximately one‐third of the patients (32%) had CSF l‐asparagine depletion below 0.5 μM 11 days after the second PEGasparaginase dose administration. CSF d‐asparagine and l‐glutamine levels remained stable before and after administration of PEGasparaginase. The percentage of d‐asparagine as a fraction of total asparagine (sum of d‐ and l‐asparagine) was 0.62% before and 4.5% after PEGasparaginase treatment. No correlation was found between higher serum PEGasparaginase activity and CSF l‐asparagine concentration. Conclusion l‐Asparagine is not a better parameter than total asparagine in CSF due to the negligible amount of d‐asparagine in the CSF before and after PEGasparaginase treatment.

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“…More recently, Ballerini et al showed a complete Asn depletion in serum and CSF in healthy rats with both the native L-ASNase formulations derived from E. chrysanthemi and E. coli , and to a lesser extent for PEG-L-ASNase. In addition, they demonstrated that L-ASNase enzymatic activity could be measured in the CSF and was more evident for non-PEGylated formulations, which may be explained by the difference in molecular weight between the different L-ASNase preparations [ 149 ]. These results indicate that L-ASNase may be beneficial for the treatment of brain tumors, including glioblastoma.…”

Section: Expanding the Use Of L-asnase Therapy Beyond All In Childrenmentioning

confidence: 99%

Novel Insights on the Use of L-Asparaginase as an Efficient and Safe Anti-Cancer Therapy

Trimpont

Peeters

Visser

et al. 2022

Cancers

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L-Asparaginase (L-ASNase) is an enzyme that hydrolyses the amino acid asparagine into aspartic acid and ammonia. Systemic administration of bacterial L-ASNase is successfully used to lower the bioavailability of this non-essential amino acid and to eradicate rapidly proliferating cancer cells with a high demand for exogenous asparagine. Currently, it is a cornerstone drug in the treatment of the most common pediatric cancer, acute lymphoblastic leukemia (ALL). Since these lymphoblasts lack the expression of asparagine synthetase (ASNS), these cells depend on the uptake of extracellular asparagine for survival. Interestingly, recent reports have illustrated that L-ASNase may also have clinical potential for the treatment of other aggressive subtypes of hematological or solid cancers. However, immunogenic and other severe adverse side effects limit optimal clinical use and often lead to treatment discontinuation. The design of optimized and novel L-ASNase formulations provides opportunities to overcome these limitations. In addition, identification of multiple L-ASNase resistance mechanisms, including ASNS promoter reactivation and desensitization, has fueled research into promising novel drug combinations to overcome chemoresistance. In this review, we discuss recent insights into L-ASNase adverse effects, resistance both in hematological and solid tumors, and how novel L-ASNase variants and drug combinations can expand its clinical applicability.

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Pharmacodynamic effects in the cerebrospinal fluid of rats after intravenous administration of different asparaginase formulations

Abstract: Together with the ASN depletion in serum and CSF, a never before demonstrated transient penetration of ASNases into the CSF, more evident for non-pegylated formulations, was detected when the ASNases were administered at high dose.

Cited by 5 publications

References 12 publications

Asparagine levels in the cerebrospinal fluid of children with acute lymphoblastic leukemia treated with pegylated-asparaginase in the induction phase of the AIEOP-BFM ALL 2009 study

Asparagine levels in the cerebrospinal fluid of children with acute lymphoblastic leukemia treated with pegylated-asparaginase in the induction phase of the AIEOP-BFM ALL 2009 study

Depletion of d‐ and l‐asparagine in cerebrospinal fluid in acute lymphoblastic leukemia during PEGasparaginase therapy

Novel Insights on the Use of L-Asparaginase as an Efficient and Safe Anti-Cancer Therapy

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