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.
Highlights
Glioblastoma (GB) is the most lethal brain tumor with median patients’ survival of 10–14 months [1]
In order to investigate the radiosensitization properties of NVP-BEZ235 towards orthotopic GB driven by primary glioma initiating cells (GIC) that more faithfully mimic the clinical tumors growth, [17] we preliminarily investigated the pharmacokinetics of NVPBEZ235 using High Performance Liquid Chromatography (HPLC)/mass spectrometry (MS)
Two hours after the i.p. administration of one single 25 mg/Kg body weight dose, NVP-BEZ235 could be detected in the brain of tumor-free mice at concentrations (111 × 10− 9 M) significantly higher than the IC50 for ATRi in cells (21 × 10− 9 M)[12] (Fig. 1e)
Summary
Glioblastoma (GB) is the most lethal brain tumor with median patients’ survival of 10–14 months [1]. GB recurrence and progression has been linked to specific cell populations [glioma initiating cells (GIC)] refractory to radio-and chemotherapy due to their quiescent state, from which they exit to regenerate the tumor once therapies have ceased [2, 3]. This quiescent state is attributed to constitutive activation of a DNA damage response (DDR), which leads to a number of cellular outcomes including, in a large proportion of tumor cells, cell cycle arrest at the G2/M checkpoint [4]. We report the results of a pilot radiosensitization experiment on adult GIC-driven orthotopic GBs
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