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Radiat Oncol. 2018 Apr 23;13(1):76. doi: 10.1186/s13014-018-1020-3.

ATR kinase inhibitors NVP-BEZ235 and AZD6738 effectively penetrate the brain after systemic administration.

Author information

1
Mutagenesis & Cancer Prevention, Ospedale Policlinico San Martino, Genoa, Italy. guido.frosina@hsanmartino.it.
2
Biopolymers and Proteomics, Ospedale Policlinico San Martino, Genoa, Italy.
3
Department of Experimental Medicine (DIMES), University of Genova, Genoa, Italy.
4
Mutagenesis & Cancer Prevention, Ospedale Policlinico San Martino, Genoa, Italy.
5
Pathological Anatomy and Histology, Ospedale Policlinico San Martino, Genoa, Italy.
6
Regenerative Medicine, Ospedale Policlinico San Martino, Genoa, Italy.

Abstract

Ataxia Telangiectasia and Rad3 related protein (ATR) is a central mediator of the response to DNA damage that may cause the quiescent resistance of cancer initiating cells to genotoxic radiotherapy. NVP-BEZ235 is a dual PI3K/mTOR inhibitor that also effectively targets ATR with IC50 = 21 × 10- 9 M in cells. AZD6738 does not target significantly PI3K/mTOR-related kinases but specifically inhibits ATR with IC50 = 74 × 10- 9 M in cells. Both drugs have been proposed as radiosensitizers of different tumors including glioblastoma (GB), the most malignant brain tumor. In order to study the radiosensitizing properties of ATR inhibitors NVP-BEZ235 and AZD6738 towards GB, we have preliminarily investigated their capacity to penetrate the brain after systemic administration. Tumor-free CD-1 mice were inoculated i.p. with 25 mg/Kg body weight of NVP-BEZ235 or AZD6738. 1, 2, 6 and 8 h later, blood was collected by retro-orbital bleeding after which the mice were euthanized and the brains explanted. Blood and brain samples were then extracted and NVP-BEZ235 and AZD6738 concentrations determined by High Performance Liquid Chromatography/Mass Spectrometry. We found for NVP-BEZ235 and especially for AZD6738, elevated bioavailability and effective brain penetration after intraperitoneal administration. Albeit low drug and radiation dosages were used, a trend to toxicity of NVP-BEZ235 followed by ionizing radiation (IR) towards mice bearing primary glioma initiating cells (GIC)-driven orthotopic tumors was yet observed, as compared to AZD6738 + IR and vehicle+IR. Survival was never improved with median values of 99, 86 and 101 days for vehicle+IR, NVP-BEZ235 + IR and AZD6738 + IR-treated mice, respectively. Although the present results indicate favorable pharmacokinetics properties of ATR inhibitors NVP-BEZ235 and AZD6738, they do not lend support to their use as radiosensitizers of GB.

KEYWORDS:

Ataxia Telangiectasia and Rad3 related protein; blood brain barrier; pharmacokinetics

PMID:
29685176
PMCID:
PMC5914052
DOI:
10.1186/s13014-018-1020-3
[Indexed for MEDLINE]
Free PMC Article

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