The effects of extra high dose rate irradiation on glioma stem-like cells.

Radiation therapy is an integral part of treatment for patients with glioblastoma. New technological advances in linear accelerators have made extra-high dose rate irradiation possible. This shortens patient treatment time significantly compared to standard dose rate irradiation, but the biologic effects of extra high dose rate irradiation are poorly understood. Glioma stem-like cells (GSCs) are resistant to standard radiation and contribute to tumor progression. Here, we assess the therapeutic effect of extra high dose rate vs. standard dose rate irradiation on GSCs. GSCs were exposed to 2, 4 and 6 Gy X-irradiation at dose rates of 4.2 Gy/min or 21.2 Gy/min (400 monitoring units (MU)/min or 2100 MU/min). We analyzed cell survival with cell growth assays, tumorsphere formation assays and colony formation assays. Cell kill and self-renewal were dependent on the total dose of radiation delivered. However, there was no difference in survival of GSCs or DNA damage repair in GSCs irradiated at different dose rates. GSCs exhibited significant G1 and G2/M phase arrest and increased apoptosis with higher doses of radiation but there was no difference between the two dose rates at each given dose. In a GSC-derived preclinical model of glioblastoma, radiation extended animal survival, but there was no difference in survival in mice receiving different dose rates of radiation. We conclude that GSCs respond to larger fractions of radiation, but extra high dose rate irradiation has no significant biologic advantage in comparison with standard dose rate irradiation.