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

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

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.

MeSH terms

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

Substances

  • AZD6738
  • Antineoplastic Agents
  • Imidazoles
  • Pyrimidines
  • Quinolines
  • Radiation-Sensitizing Agents
  • Sulfoxides
  • ATR protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • dactolisib