Central Nervous System Distribution of the Ataxia-Telangiectasia Mutated Kinase Inhibitor AZD1390: Implications for the Treatment of Brain Tumors
Journal of Pharmacology and Experimental Therapeutics
; 383(1):91-102, 2022.
Article
in English
| EMBASE | ID: covidwho-2304523
ABSTRACT
Effective drug delivery to the brain is critical for the treatment of glioblastoma (GBM), an aggressive and invasive primary brain tumor that has a dismal prognosis. Radiation therapy, the mainstay of brain tumor treatment, works by inducing DNA damage. Therefore, inhibiting DNA damage response (DDR) pathways can sensitize tumor cells to radiation and enhance cytotoxicity. AZD1390 is an inhibitor of ataxia-telangiectasia mutated kinase, a critical regulator of DDR. Our in vivo studies in the mouse indicate that delivery of AZD1390 to the central nervous system (CNS) is restricted due to active efflux by P-glycoprotein (P-gp). The free fraction of AZD1390 in brain and spinal cord were found to be low, thereby reducing the partitioning of free drug to these organs. Coadministration of an efflux inhibitor significantly increased CNS exposure of AZD1390. No differences were observed in distribution of AZD1390 within different anatomic regions of CNS, and the functional activity of P-gp and breast cancer resistance protein also remained the same across brain regions. In an intracranial GBM patient-derived xenograft model, AZD1390 accumulation was higher in the tumor core and rim compared with surrounding brain. Despite this heterogenous delivery within tumor-bearing brain, AZD1390 concentrations in normal brain, tumor rim, and tumor core were above in vitro effective radiosensitizing concentrations. These results indicate that despite being a substrate of efflux in the mouse brain, sufficient AZD1390 exposure is anticipated even in regions of normal brain. SIGNIFICANCE STATEMENT Given the invasive nature of glioblastoma (GBM), tumor cells are often protected by an intact blood-brain barrier, requiring the development of brain-penetrant molecules for effective treatment. We show that efflux mediated by P-glycoprotein (P-gp) limits central nervous system (CNS) distribution of AZD1390 and that there are no distributional differences within anatomical regions of CNS. Despite efflux by P-gp, concentrations effective for potent radiosensitization are achieved in GBM tumor-bearing mouse brains, indicating that AZD1390 is an attractive molecule for clinical development of brain tumors.Copyright © 2022 American Society for Pharmacology and Experimental Therapy. All rights reserved.
animal experiment; animal model; area under the curve; article; bioavailability; brain stem; brain tumor; cell cycle; central nervous system; controlled study; cytotoxicity; DNA damage; DNA damage response; drug formulation; female; fluorescence intensity; genotype; glioblastoma; high performance liquid chromatography; in vitro study; in vivo study; leukemia; limit of quantitation; liquid chromatography-mass spectrometry; male; mean residence time; mouse; nonhuman; pharmacokinetics; radiosensitization; steady state; thalamus; tumor cell; xenograft; ABC transporter subfamily B/ec [Endogenous Compound]; ATM protein/ec [Endogenous Compound]; breast cancer resistance protein/ec [Endogenous Compound]; dasatinib/ec [Endogenous Compound]; elacridar/ec [Endogenous Compound]; formic acid/ec [Endogenous Compound]; hydroxypropylmethylcellulose; polysorbate 80/po [Oral Drug Administration]; protein kinase inhibitor; radiosensitizing agent/ec [Endogenous Compound]; unclassified drug; vaxzevria; high performance liquid chromatograph; mass spectrometer; astrazeneca; azd1390; acquity; Quattro Ultima
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Databases of international organizations
Database:
EMBASE
Language:
English
Journal:
Journal of Pharmacology and Experimental Therapeutics
Year:
2022
Document Type:
Article
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