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

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Abstract

Purpose

Asparaginase (ASNase) is used to treat various hematological malignancies for its capacity to deplete asparagine (ASN) in serum and cerebrospinal fluid (CSF). Since the biological mechanisms underlying CSF asparagine depletion in humans are not yet fully elucidated, this study compared, for the first time, the pharmacological properties of three clinically used ASNase formulations in a rodent model.

Methods

Male Wistar rats were treated with E.coli-ASNase, PEG-ASNase, or ERW-ASNase at different doses. Serum and CSF amino-acid levels and ASNase activities were evaluated at 1 and 24 h after the intravenous administration of different ASNase doses.

Results

All the ASNase formulations showed higher activities in serum after 1 h than 24 h and completely deplete ASN. Mean ASNase activity in the CSF at 1 h was higher with ERW-ASNase compared to PEG-ASNase (36 ± 29 vs 8 ± 7 U/L, p < 0.037) and similar to E.coli-ASNase (21 ± 9 U/L, ns). ERW-ASNase and E.coli-ASNase at the highest doses were able to deplete ASN in the CSF after 1 h. This effect was transient and not evident at 24 h after treatment.

Conclusions

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.

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Acknowledgements

The authors would like to thank the Comitato Maria Letizia Verga for the support to the research activities in the field of childhood leukemia. We also thank Carly S. Filgueira for critical editing of the manuscript.

Author information

Author notes

  1. Massimo Zucchetti and Carmelo Rizzari equally contributed to this work.

Authors and Affiliations

  1. Clinical Cancer Pharmacology Unit, Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Via La Masa 19, 20156, Milan, Italy

    Andrea Ballerini, Ilaria Fuso Nerini, Mariella Ferrari, Maurizio D’Incalci, Luca Porcu & Massimo Zucchetti

  2. Department of Oncology and Onco-Hematology, University of Milan, Milan, Italy

    Andrea Ballerini

  3. Experimental Psychopharmacology, Department of Neuroscience, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy

    Federico Moro, Claudio Marcello Marzo, Angelo Di Clemente & Luigi Cervo

  4. Pediatric Hematology-Oncology Unit, Department of Pediatrics, University of Milano-Bicocca, MBBM Foundation, ASST Monza, Monza, Italy

    Andrea Biondi, Antonella Colombini, Valentino Conter & Carmelo Rizzari

Authors
  1. Andrea Ballerini
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  2. Federico Moro
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  3. Ilaria Fuso Nerini
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  6. Mariella Ferrari
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  7. Maurizio D’Incalci
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  9. Antonella Colombini
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  11. Luca Porcu
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  12. Luigi Cervo
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  13. Carmelo Rizzari
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  14. Massimo Zucchetti
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Contributions

AB designed the study, performed research, analyzed data, and wrote the manuscript. IFN performed research, analyzed data, and helped writing the manuscript. FM, CMM, ADC, and MF performed research. MD, AB, AC, VC, and LC analyzed the data, helped designing the study, and writing the manuscript. LP analyzed the data. CR and MZ designed the study, analyzed data, and wrote the manuscript. All authors discussed the results.

Corresponding author

Correspondence to Massimo Zucchetti.

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Conflict of interest

All the authors declare no conflict of interest.

Ethical approval

Animal experiments has been reviewed and approved by the IRFMN Animal Care and Use Committee (IACUC) that includes members “ad hoc” for ethical issues. The procedures involving animals and their care were conducted in conformity with Italian Governing Law D.lgs 26/2014 and EEC Council Directive 2010/63/UE. All this information is included in the manuscript.

Electronic supplementary material

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280_2017_3307_MOESM1_ESM.pptx

Analysis of red blood cells (RBC) number in the CSF to exclude possible blood–CSF contamination during sampling. The represented CSF samples were collected at 1 h (A) and 24 h (B) after ASNases injection and had been analyzed with a Bürker counting chamber. No correlation was observed between CSF RBC number and CSF ASNase activity at 1 h (C). Since all the CSF ASNase activities at 24 h were 0 U/L for all the samples, it was impossible to look for correlation at that time point (PPTX 331 kb)

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Ballerini, A., Moro, F., Nerini, I.F. et al. Pharmacodynamic effects in the cerebrospinal fluid of rats after intravenous administration of different asparaginase formulations. Cancer Chemother Pharmacol 79, 1267–1271 (2017). https://doi.org/10.1007/s00280-017-3307-8

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  • DOI: https://doi.org/10.1007/s00280-017-3307-8

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