Andrea Ballerini1,2, Federico Moro3, Ilaria Fuso Nerini1, Claudio Marcello Marzo3, Angelo Di Clemente3, Mariella Ferrari1, Maurizio D'Incalci1, Andrea Biondi4, Antonella Colombini4, Valentino Conter4, Luca Porcu1, Luigi Cervo3, Carmelo Rizzari4, Massimo Zucchetti5. 1. Clinical Cancer Pharmacology Unit, Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Via La Masa 19, 20156, Milan, Italy. 2. Department of Oncology and Onco-Hematology, University of Milan, Milan, Italy. 3. Experimental Psychopharmacology, Department of Neuroscience, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy. 4. Pediatric Hematology-Oncology Unit, Department of Pediatrics, University of Milano-Bicocca, MBBM Foundation, ASST Monza, Monza, Italy. 5. 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.
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.
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.
Authors: Maaike Van Trimpont; Evelien Peeters; Yanti De Visser; Amanda M Schalk; Veerle Mondelaers; Barbara De Moerloose; Arnon Lavie; Tim Lammens; Steven Goossens; Pieter Van Vlierberghe Journal: Cancers (Basel) Date: 2022-02-11 Impact factor: 6.639
Authors: Carmelo Rizzari; Claudia Lanvers-Kaminsky; Maria Grazia Valsecchi; Andrea Ballerini; Cristina Matteo; Joachim Gerss; Gudrun Wuerthwein; Daniela Silvestri; Antonella Colombini; Valentino Conter; Andrea Biondi; Martin Schrappe; Anja Moericke; Martin Zimmermann; Arend von Stackelberg; Christin Linderkamp; Michael C Frühwald; Sabine Legien; Andishe Attarbaschi; Bettina Reismüller; David Kasper; Petr Smisek; Jan Stary; Luciana Vinti; Elena Barisone; Rosanna Parasole; Concetta Micalizzi; Massimo Zucchetti; Joachim Boos Journal: Haematologica Date: 2019-01-31 Impact factor: 9.941