Pharmacokinetics, pharmacodynamics and efficacy on pediatric tumors of the glioma radiosensitizer KU60019

Donatella Vecchio, Antonio Daga, Elisa Carra, Daniela Marubbi, Alessandro Raso, Samantha Mascelli, Paolo Nozza, Maria Luisa Garre, Francesca Pitto, Jean Louis Ravetti, Stefano Vagge, Renzo Corvo, Aldo Profumo, Gabriella Baio, Diana Marcello, Guido Frosina*

*Corresponding author for this work

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

We have recently reported that glioblastoma (GB)-initiating cells (GIC) with low expression and/or mutation of TP53 and high expression of PI3K (responder genetic profile) can be effectively and safely radiosensitized by the ATM inhibitor KU60019. We report here on drug's diffusion and elimination from the animal body and brain, its effects on orthotopic GB and efficacy toward pediatric GIC. Healthy mice were infused by convection enhanced delivery (CED) with KU60019 and the drug kinetics followed by high performance liquid chromatography-mass spectrometry. Already at the end of CED, KU60019 had diffused from the injection site to the ipsilateral and, to a lower extent, controlateral hemisphere. After 24 hr, no drug could be detected all over the brain or in other organs, indicating rapid draining and excretion. After intraperitoneal injection, traces only of KU60019 could be detected in the brain, indicating inability to cross the brain-blood barrier. Consistent with the induction of cell cycle progression previously observed in vitro, KU60019 stimulated proliferation of orthotopic GB cells with the highest effect observed 96 hr after drug delivery. Adult GIC with high expression of TP53 and low expression of PI3K could be radiosensitized by KU60019, although less promptly than GIC bearing the responder profile. Consistent with the kinetics of proliferation induction, the highest radiosensitizing effect was observed 96 hr after delivery of KU60019 to GIC. Pediatric GIC could be similarly radiosensitized after exposure to KU60019. The results indicate that ATM inhibition may allow to radiosensitize a wide range of adult and pediatric high-grade gliomas.

What's new? Quiescent glioblastoma-initiating cells (GIC) are a likely source of resistance to radiotherapy in glioblastoma, suggesting that sensitization of GIC to ionizing radiation could help mitigate the invariably lethal nature of the disease. KU60019, an inhibitor of the ataxia telangiectasia mutated (ATM) kinase, activation of which helps regulate radioresistance in GIC, is a promising radiosensitizing agent in glioblastoma. This study describes the biodistribution of KU60019 in the animal body and brain following intracerebral delivery via an electric pump. In an orthotopic model, KU60019 demonstrated radiosensitizing effects within 96 hours of delivery. Similar effects were observed in pediatric high-grade gliomas.

Original languageEnglish
Pages (from-to)1445-1457
Number of pages13
JournalInternational Journal of Cancer
Volume136
Issue number6
Early online date11 Aug 2014
DOIs
Publication statusPublished - 15 Mar 2015

Keywords

  • pharmacokinetics
  • pharmacodynamics
  • pediatric
  • glioblastoma
  • anaplastic astrocytoma
  • radiotherapy
  • ataxia telangiectasia mutated
  • inhibition
  • sensitization
  • malignant gliomas
  • initiating cells
  • ATM inhibitor
  • human cancer
  • stem-cells
  • repair
  • mutations
  • therapy

Cite this

Vecchio, D., Daga, A., Carra, E., Marubbi, D., Raso, A., Mascelli, S., ... Frosina, G. (2015). Pharmacokinetics, pharmacodynamics and efficacy on pediatric tumors of the glioma radiosensitizer KU60019. International Journal of Cancer, 136(6), 1445-1457. https://doi.org/10.1002/ijc.29121

Pharmacokinetics, pharmacodynamics and efficacy on pediatric tumors of the glioma radiosensitizer KU60019. / Vecchio, Donatella; Daga, Antonio; Carra, Elisa; Marubbi, Daniela; Raso, Alessandro; Mascelli, Samantha; Nozza, Paolo; Garre, Maria Luisa; Pitto, Francesca; Ravetti, Jean Louis; Vagge, Stefano; Corvo, Renzo; Profumo, Aldo; Baio, Gabriella; Marcello, Diana; Frosina, Guido.

In: International Journal of Cancer, Vol. 136, No. 6, 15.03.2015, p. 1445-1457.

Research output: Contribution to journalArticle

Vecchio, D, Daga, A, Carra, E, Marubbi, D, Raso, A, Mascelli, S, Nozza, P, Garre, ML, Pitto, F, Ravetti, JL, Vagge, S, Corvo, R, Profumo, A, Baio, G, Marcello, D & Frosina, G 2015, 'Pharmacokinetics, pharmacodynamics and efficacy on pediatric tumors of the glioma radiosensitizer KU60019', International Journal of Cancer, vol. 136, no. 6, pp. 1445-1457. https://doi.org/10.1002/ijc.29121
Vecchio, Donatella ; Daga, Antonio ; Carra, Elisa ; Marubbi, Daniela ; Raso, Alessandro ; Mascelli, Samantha ; Nozza, Paolo ; Garre, Maria Luisa ; Pitto, Francesca ; Ravetti, Jean Louis ; Vagge, Stefano ; Corvo, Renzo ; Profumo, Aldo ; Baio, Gabriella ; Marcello, Diana ; Frosina, Guido. / Pharmacokinetics, pharmacodynamics and efficacy on pediatric tumors of the glioma radiosensitizer KU60019. In: International Journal of Cancer. 2015 ; Vol. 136, No. 6. pp. 1445-1457.
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abstract = "We have recently reported that glioblastoma (GB)-initiating cells (GIC) with low expression and/or mutation of TP53 and high expression of PI3K (responder genetic profile) can be effectively and safely radiosensitized by the ATM inhibitor KU60019. We report here on drug's diffusion and elimination from the animal body and brain, its effects on orthotopic GB and efficacy toward pediatric GIC. Healthy mice were infused by convection enhanced delivery (CED) with KU60019 and the drug kinetics followed by high performance liquid chromatography-mass spectrometry. Already at the end of CED, KU60019 had diffused from the injection site to the ipsilateral and, to a lower extent, controlateral hemisphere. After 24 hr, no drug could be detected all over the brain or in other organs, indicating rapid draining and excretion. After intraperitoneal injection, traces only of KU60019 could be detected in the brain, indicating inability to cross the brain-blood barrier. Consistent with the induction of cell cycle progression previously observed in vitro, KU60019 stimulated proliferation of orthotopic GB cells with the highest effect observed 96 hr after drug delivery. Adult GIC with high expression of TP53 and low expression of PI3K could be radiosensitized by KU60019, although less promptly than GIC bearing the responder profile. Consistent with the kinetics of proliferation induction, the highest radiosensitizing effect was observed 96 hr after delivery of KU60019 to GIC. Pediatric GIC could be similarly radiosensitized after exposure to KU60019. The results indicate that ATM inhibition may allow to radiosensitize a wide range of adult and pediatric high-grade gliomas.What's new? Quiescent glioblastoma-initiating cells (GIC) are a likely source of resistance to radiotherapy in glioblastoma, suggesting that sensitization of GIC to ionizing radiation could help mitigate the invariably lethal nature of the disease. KU60019, an inhibitor of the ataxia telangiectasia mutated (ATM) kinase, activation of which helps regulate radioresistance in GIC, is a promising radiosensitizing agent in glioblastoma. This study describes the biodistribution of KU60019 in the animal body and brain following intracerebral delivery via an electric pump. In an orthotopic model, KU60019 demonstrated radiosensitizing effects within 96 hours of delivery. Similar effects were observed in pediatric high-grade gliomas.",
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author = "Donatella Vecchio and Antonio Daga and Elisa Carra and Daniela Marubbi and Alessandro Raso and Samantha Mascelli and Paolo Nozza and Garre, {Maria Luisa} and Francesca Pitto and Ravetti, {Jean Louis} and Stefano Vagge and Renzo Corvo and Aldo Profumo and Gabriella Baio and Diana Marcello and Guido Frosina",
note = "Acknowledgements The authors thank Mr. Angelo Carra (NUOVA CI-TRE SNC, Reggio Emilia, Italy) for modification of BeeHive pump allowing multiple CED, Dr. Carmine T. Recchiuto (HUMANOT SRL, Prato, Italy) for development of software allowing calculation of MPC and Dr. Carlo Scapolla, Department of Chemistry, University of Genova, for helpful discussion of HPLC/MS data. D.V. is the recipient of a “Young Investigator Programme” fellowship from Fondazione Umberto Veronesi, Milano, Italy. A.R. and S.M. are the recipients of fellowships from Associazione Italiana Ricerca Tumori Cerebrali del Bambino, Genova, Italy.",
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T1 - Pharmacokinetics, pharmacodynamics and efficacy on pediatric tumors of the glioma radiosensitizer KU60019

AU - Vecchio, Donatella

AU - Daga, Antonio

AU - Carra, Elisa

AU - Marubbi, Daniela

AU - Raso, Alessandro

AU - Mascelli, Samantha

AU - Nozza, Paolo

AU - Garre, Maria Luisa

AU - Pitto, Francesca

AU - Ravetti, Jean Louis

AU - Vagge, Stefano

AU - Corvo, Renzo

AU - Profumo, Aldo

AU - Baio, Gabriella

AU - Marcello, Diana

AU - Frosina, Guido

N1 - Acknowledgements The authors thank Mr. Angelo Carra (NUOVA CI-TRE SNC, Reggio Emilia, Italy) for modification of BeeHive pump allowing multiple CED, Dr. Carmine T. Recchiuto (HUMANOT SRL, Prato, Italy) for development of software allowing calculation of MPC and Dr. Carlo Scapolla, Department of Chemistry, University of Genova, for helpful discussion of HPLC/MS data. D.V. is the recipient of a “Young Investigator Programme” fellowship from Fondazione Umberto Veronesi, Milano, Italy. A.R. and S.M. are the recipients of fellowships from Associazione Italiana Ricerca Tumori Cerebrali del Bambino, Genova, Italy.

PY - 2015/3/15

Y1 - 2015/3/15

N2 - We have recently reported that glioblastoma (GB)-initiating cells (GIC) with low expression and/or mutation of TP53 and high expression of PI3K (responder genetic profile) can be effectively and safely radiosensitized by the ATM inhibitor KU60019. We report here on drug's diffusion and elimination from the animal body and brain, its effects on orthotopic GB and efficacy toward pediatric GIC. Healthy mice were infused by convection enhanced delivery (CED) with KU60019 and the drug kinetics followed by high performance liquid chromatography-mass spectrometry. Already at the end of CED, KU60019 had diffused from the injection site to the ipsilateral and, to a lower extent, controlateral hemisphere. After 24 hr, no drug could be detected all over the brain or in other organs, indicating rapid draining and excretion. After intraperitoneal injection, traces only of KU60019 could be detected in the brain, indicating inability to cross the brain-blood barrier. Consistent with the induction of cell cycle progression previously observed in vitro, KU60019 stimulated proliferation of orthotopic GB cells with the highest effect observed 96 hr after drug delivery. Adult GIC with high expression of TP53 and low expression of PI3K could be radiosensitized by KU60019, although less promptly than GIC bearing the responder profile. Consistent with the kinetics of proliferation induction, the highest radiosensitizing effect was observed 96 hr after delivery of KU60019 to GIC. Pediatric GIC could be similarly radiosensitized after exposure to KU60019. The results indicate that ATM inhibition may allow to radiosensitize a wide range of adult and pediatric high-grade gliomas.What's new? Quiescent glioblastoma-initiating cells (GIC) are a likely source of resistance to radiotherapy in glioblastoma, suggesting that sensitization of GIC to ionizing radiation could help mitigate the invariably lethal nature of the disease. KU60019, an inhibitor of the ataxia telangiectasia mutated (ATM) kinase, activation of which helps regulate radioresistance in GIC, is a promising radiosensitizing agent in glioblastoma. This study describes the biodistribution of KU60019 in the animal body and brain following intracerebral delivery via an electric pump. In an orthotopic model, KU60019 demonstrated radiosensitizing effects within 96 hours of delivery. Similar effects were observed in pediatric high-grade gliomas.

AB - We have recently reported that glioblastoma (GB)-initiating cells (GIC) with low expression and/or mutation of TP53 and high expression of PI3K (responder genetic profile) can be effectively and safely radiosensitized by the ATM inhibitor KU60019. We report here on drug's diffusion and elimination from the animal body and brain, its effects on orthotopic GB and efficacy toward pediatric GIC. Healthy mice were infused by convection enhanced delivery (CED) with KU60019 and the drug kinetics followed by high performance liquid chromatography-mass spectrometry. Already at the end of CED, KU60019 had diffused from the injection site to the ipsilateral and, to a lower extent, controlateral hemisphere. After 24 hr, no drug could be detected all over the brain or in other organs, indicating rapid draining and excretion. After intraperitoneal injection, traces only of KU60019 could be detected in the brain, indicating inability to cross the brain-blood barrier. Consistent with the induction of cell cycle progression previously observed in vitro, KU60019 stimulated proliferation of orthotopic GB cells with the highest effect observed 96 hr after drug delivery. Adult GIC with high expression of TP53 and low expression of PI3K could be radiosensitized by KU60019, although less promptly than GIC bearing the responder profile. Consistent with the kinetics of proliferation induction, the highest radiosensitizing effect was observed 96 hr after delivery of KU60019 to GIC. Pediatric GIC could be similarly radiosensitized after exposure to KU60019. The results indicate that ATM inhibition may allow to radiosensitize a wide range of adult and pediatric high-grade gliomas.What's new? Quiescent glioblastoma-initiating cells (GIC) are a likely source of resistance to radiotherapy in glioblastoma, suggesting that sensitization of GIC to ionizing radiation could help mitigate the invariably lethal nature of the disease. KU60019, an inhibitor of the ataxia telangiectasia mutated (ATM) kinase, activation of which helps regulate radioresistance in GIC, is a promising radiosensitizing agent in glioblastoma. This study describes the biodistribution of KU60019 in the animal body and brain following intracerebral delivery via an electric pump. In an orthotopic model, KU60019 demonstrated radiosensitizing effects within 96 hours of delivery. Similar effects were observed in pediatric high-grade gliomas.

KW - pharmacokinetics

KW - pharmacodynamics

KW - pediatric

KW - glioblastoma

KW - anaplastic astrocytoma

KW - radiotherapy

KW - ataxia telangiectasia mutated

KW - inhibition

KW - sensitization

KW - malignant gliomas

KW - initiating cells

KW - ATM inhibitor

KW - human cancer

KW - stem-cells

KW - repair

KW - mutations

KW - therapy

U2 - 10.1002/ijc.29121

DO - 10.1002/ijc.29121

M3 - Article

VL - 136

SP - 1445

EP - 1457

JO - International Journal of Cancer

JF - International Journal of Cancer

SN - 0020-7136

IS - 6

ER -