PMID- 28424964
OWN - NLM
STAT- MEDLINE
DCOM- 20170613
LR  - 20201209
IS  - 1432-0843 (Electronic)
IS  - 0344-5704 (Linking)
VI  - 79
IP  - 6
DP  - 2017 Jun
TI  - Pharmacodynamic effects in the cerebrospinal fluid of rats after intravenous 
      administration of different asparaginase formulations.
PG  - 1267-1271
LID - 10.1007/s00280-017-3307-8 [doi]
AB  - 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.
FAU - Ballerini, Andrea
AU  - Ballerini A
AD  - Clinical Cancer Pharmacology Unit, Department of Oncology, IRCCS-Istituto di 
      Ricerche Farmacologiche Mario Negri, Via La Masa 19, 20156, Milan, Italy.
AD  - Department of Oncology and Onco-Hematology, University of Milan, Milan, Italy.
FAU - Moro, Federico
AU  - Moro F
AD  - Experimental Psychopharmacology, Department of Neuroscience, IRCCS-Istituto di 
      Ricerche Farmacologiche Mario Negri, Milan, Italy.
FAU - Nerini, Ilaria Fuso
AU  - Nerini IF
AD  - Clinical Cancer Pharmacology Unit, Department of Oncology, IRCCS-Istituto di 
      Ricerche Farmacologiche Mario Negri, Via La Masa 19, 20156, Milan, Italy.
FAU - Marzo, Claudio Marcello
AU  - Marzo CM
AD  - Experimental Psychopharmacology, Department of Neuroscience, IRCCS-Istituto di 
      Ricerche Farmacologiche Mario Negri, Milan, Italy.
FAU - Di Clemente, Angelo
AU  - Di Clemente A
AD  - Experimental Psychopharmacology, Department of Neuroscience, IRCCS-Istituto di 
      Ricerche Farmacologiche Mario Negri, Milan, Italy.
FAU - Ferrari, Mariella
AU  - Ferrari M
AD  - Clinical Cancer Pharmacology Unit, Department of Oncology, IRCCS-Istituto di 
      Ricerche Farmacologiche Mario Negri, Via La Masa 19, 20156, Milan, Italy.
FAU - D'Incalci, Maurizio
AU  - D'Incalci M
AD  - Clinical Cancer Pharmacology Unit, Department of Oncology, IRCCS-Istituto di 
      Ricerche Farmacologiche Mario Negri, Via La Masa 19, 20156, Milan, Italy.
FAU - Biondi, Andrea
AU  - Biondi A
AD  - Pediatric Hematology-Oncology Unit, Department of Pediatrics, University of 
      Milano-Bicocca, MBBM Foundation, ASST Monza, Monza, Italy.
FAU - Colombini, Antonella
AU  - Colombini A
AD  - Pediatric Hematology-Oncology Unit, Department of Pediatrics, University of 
      Milano-Bicocca, MBBM Foundation, ASST Monza, Monza, Italy.
FAU - Conter, Valentino
AU  - Conter V
AD  - Pediatric Hematology-Oncology Unit, Department of Pediatrics, University of 
      Milano-Bicocca, MBBM Foundation, ASST Monza, Monza, Italy.
FAU - Porcu, Luca
AU  - Porcu L
AD  - Clinical Cancer Pharmacology Unit, Department of Oncology, IRCCS-Istituto di 
      Ricerche Farmacologiche Mario Negri, Via La Masa 19, 20156, Milan, Italy.
FAU - Cervo, Luigi
AU  - Cervo L
AD  - Experimental Psychopharmacology, Department of Neuroscience, IRCCS-Istituto di 
      Ricerche Farmacologiche Mario Negri, Milan, Italy.
FAU - Rizzari, Carmelo
AU  - Rizzari C
AD  - Pediatric Hematology-Oncology Unit, Department of Pediatrics, University of 
      Milano-Bicocca, MBBM Foundation, ASST Monza, Monza, Italy.
FAU - Zucchetti, Massimo
AU  - Zucchetti M
AUID- ORCID: 0000-0002-5427-052X
AD  - Clinical Cancer Pharmacology Unit, Department of Oncology, IRCCS-Istituto di 
      Ricerche Farmacologiche Mario Negri, Via La Masa 19, 20156, Milan, Italy. 
      massimo.zucchetti@marionegri.it.
LA  - eng
PT  - Journal Article
DEP - 20170419
PL  - Germany
TA  - Cancer Chemother Pharmacol
JT  - Cancer chemotherapy and pharmacology
JID - 7806519
RN  - 0 (Antineoplastic Agents)
RN  - 3WJQ0SDW1A (Polyethylene Glycols)
RN  - 7D96IR0PPM (pegaspargase)
RN  - EC 3.5.1.1 (Asparaginase)
SB  - IM
MH  - Administration, Intravenous
MH  - Animals
MH  - Antineoplastic Agents/administration & dosage/*cerebrospinal 
      fluid/*pharmacokinetics
MH  - Asparaginase/administration & dosage/*cerebrospinal fluid/*pharmacokinetics
MH  - Blood-Brain Barrier/metabolism
MH  - Dickeya chrysanthemi/enzymology
MH  - Drug Compounding
MH  - Escherichia coli/enzymology
MH  - Half-Life
MH  - Male
MH  - Molecular Weight
MH  - Polyethylene Glycols/chemistry
MH  - Rats
MH  - Rats, Wistar
OTO - NOTNLM
OT  - Asparaginase activity
OT  - Asparagine depletion
OT  - Blood-brain barrier
OT  - Cerebrospinal fluid
OT  - Pharmacology
EDAT- 2017/04/21 06:00
MHDA- 2017/06/14 06:00
CRDT- 2017/04/21 06:00
PHST- 2017/02/14 00:00 [received]
PHST- 2017/04/11 00:00 [accepted]
PHST- 2017/04/21 06:00 [pubmed]
PHST- 2017/06/14 06:00 [medline]
PHST- 2017/04/21 06:00 [entrez]
AID - 10.1007/s00280-017-3307-8 [pii]
AID - 10.1007/s00280-017-3307-8 [doi]
PST - ppublish
SO  - Cancer Chemother Pharmacol. 2017 Jun;79(6):1267-1271. doi: 
      10.1007/s00280-017-3307-8. Epub 2017 Apr 19.