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

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.

• Authors: Guido Fròsina, Aldo Profumo, Daniela Marubbi, Diana Marcello, Jean Louis Ravetti, Antonio Daga
• Journal: Radiation oncology (London, England) (Radiat Oncol) Vol. 13 Issue 1 Pg. 76 (Apr 23 2018) ISSN: 1748-717X [Electronic] England
• PMID: 29685176 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Imidazoles
• Indoles
• Morpholines
• Pyrimidines
• Quinolines
• Radiation-Sensitizing Agents
• Sulfonamides
• Sulfoxides
• ceralasertib
• ATR protein, human
• Ataxia Telangiectasia Mutated Proteins
• dactolisib

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Ataxia Telangiectasia Mutated Proteins (antagonists & inhibitors)
• Brain (drug effects, metabolism, pathology)
• Brain Neoplasms (drug therapy, metabolism, pathology)
• Glioblastoma (drug therapy, metabolism, pathology)
• Humans
• Imidazoles (pharmacology)
• Indoles
• Male
• Mice
• Middle Aged
• Morpholines
• Pyrimidines (pharmacology)
• Quinolines (pharmacology)
• Radiation-Sensitizing Agents (pharmacology)
• Signal Transduction
• Sulfonamides
• Sulfoxides (pharmacology)
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays