HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

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

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.
AuthorsDonatella Vecchio, Antonio Daga, Elisa Carra, Daniela Marubbi, Alessandro Raso, Samantha Mascelli, Paolo Nozza, Maria Luisa Garrè, Francesca Pitto, Jean Louis Ravetti, Stefano Vagge, Renzo Corvò, Aldo Profumo, Gabriella Baio, Diana Marcello, Guido Frosina
JournalInternational journal of cancer (Int J Cancer) Vol. 136 Issue 6 Pg. 1445-57 (Mar 15 2015) ISSN: 1097-0215 [Electronic] United States
PMID25091220 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Copyright© 2014 UICC.
Chemical References
  • 2-(2,6-dimethylmorpholin-4-yl)-N-(5-(6-morpholin-4-yl-4-oxo-4H-pyran-2-yl)-9H-thioxanthen-2-yl)acetamide
  • Ki-67 Antigen
  • Morpholines
  • Radiation-Sensitizing Agents
  • Thioxanthenes
  • Ataxia Telangiectasia Mutated Proteins
Topics
  • Adult
  • Animals
  • Ataxia Telangiectasia Mutated Proteins (antagonists & inhibitors)
  • Brain Neoplasms (drug therapy, pathology)
  • Child
  • Glioma (drug therapy, pathology)
  • Humans
  • Ki-67 Antigen (analysis)
  • Mice
  • Morpholines (pharmacokinetics, pharmacology, toxicity)
  • Radiation-Sensitizing Agents (pharmacokinetics)
  • Thioxanthenes (pharmacokinetics, pharmacology, toxicity)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: