Differential effects of radiation fractionation regimens on glioblastoma

Abstract

Background Radiotherapy (RT) is a mainstay of treatment for patients with glioblastoma (GB). Early clinical trials show that short course hypofractionation showed no survival benefit compared to conventional regimens with or without temozolomide chemotherapy (TMZ) but reduces the number of doses required. Concerns around delayed neurological deficits and reduced cognition from short course hypofractionated RT remain a concern. The aim of this study was to evaluate the effect of increased interfractional time using two different radiation fractionation regimens on GB. Methods The radiobiological effect of increasing doses 0–20 Gy x-ray photon RT on Gl261 and CT2A GB cell lines was compared by colony forming assay, DNA damage by alkaline comet assay, oxidative stress, DNA damage, cell cycle, and caspase-3/7 by MUSE® flow cytometric analyses, and protein expression by western blot analyses. Conventional (20 Gy/10 fractions) and hypofractionated (20 Gy/4 fractions spaced 72 h apart) RT regimens with and without TMZ (200 mg/kg/day) were performed in syngeneic Gl261 and CT2A intracranial mouse models using the Small Animal Radiation Research Platform (Xstrahl Inc.). Results X-ray photon radiation dose-dependently increased reactive oxygen species, DNA damage, autophagy, and caspase 3/7-mediated apoptotic cell death. While the conventional fractionated dose regimen of 20 Gy/10 f was effective at inducing cell death via the above mechanism, this was exceeded by a 20 Gy/4 f regimen which improved median survival and histopathology in Gl261-tumor bearing mice, and eradicated tumors in CT2A tumors with no additional toxicity. Conclusions Spacing of hypofractionated RT doses 72 h apart showed increased median survival and tumor control via increased activation of RT-mediated cell death, with no observed increased in radiotoxicity. This supports further exploration of differential RT fractionated regimens in GB clinical trials to reduce delayed neurological radiotoxicity.

Effectiveness of hypofractionated and normofractionated radiotherapy in a triple‐negative breast cancer model

“…Regarding biological effects of exposure to ionizing radiation, most studies either utilize a single-irradiation dose or focus on fractionated irradiation, applying more fractions over a short time period, to establish surviving/resistant cell lines ( 35 ). Direct radiobiological comparison of fractionation regimens, for instance, in non-small cell lung cancer or glioblastoma cell models reflects the clinical situation with some advantages of hypofractionation for tumor control with no observed increase in radiotoxicity ( 36 , 37 ). However, there is some evidence that hypofractionated radiotherapy can play a significant role in radioresistance and tumor recurrence and there is a need to optimize radiotherapy strategies, since different sites and types of tumors may respond differently to the same dose and fractionated irradiation ( 38 ).…”

Effect of Autophagy Inhibitors on Radiosensitivity in DNA Repair-Proficient and -Deficient Glioma Cells

“…Lastly, an explanation of the difference that might be observed in the clinic is based on the clinical use of fractionated radiation, in comparison to a single dose. This recently led to the proposal to use hyofractionated radiotherapy regimens, with sufficient spacing to avoid the differential outcomes in cell stress responses to therapy [ 58 ], and/or the use of pro-apoptotic compounds to enhance the efficacy of radiotherapy [ 59 , 60 ].…”

An Examination of the Anti-Cancer Properties of Plant Cannabinoids in Preclinical Models of Mesothelioma

“…After treatment, cells were harvested, washed with 1X PBS, fixed with 1 mL of ice-cold 70% ethanol and stored at −20 °C overnight. The fixed cells were stained and analysed using the MUSE ® Cell Cycle Kit and the MUSE ® Cell Analyser following the manufacturer’s instructions [ 26 ]. The percentage of cells in G0/G1, S and G2/M phases was assessed.…”