From clinical to synchrotron irradiations: boosting brain cancer treatment though a synergistic combination of TMZ and BrUdR with radiation.

Abstract

Purpose DNA incorporated bromodeoxyuridine (BrUdR) can locally enhance tumor damage when irradiated with the optimal energy for the Z of bromine in BrUdR. This research investigates the potential for improved treatment outcomes for brain cancer patients by combining the current standard treatment of radiotherapy and Temozolomide (TMZ) with DNA incorporated BrUdR and irradiation with megavoltage, kilovoltage or synchrotron radiations.Materials and methods Clonogenic assay was the endpoint for the assessment of 9LGS gliosarcoma cells pre-exposed to TMZ or BrUdR singly or co-administered. 9LGS cells were irradiated with x-rays at either clinically available low dose rate megavoltage, or orthovoltage and ultra-high dose rate synchrotron radiations. Results were supported by cell cycle, BrUdR uptake, senescence, and γH2AX double strand break analysis.Results BrUdR incorporation increased when combined with TMZ compared to 9LGS treated with BrUdR alone. For all beams tested, increased cell death was observed for 9LGS treated with BrUdR and BrUdR + TMZ with greatest radiosensitivity for 9LGS pre-exposed to BrUdR + TMZ. This correlated with additional incorporation of BrUdR and more cells in the radiosensitive G2/M phase. Maximum radiosensitivity was observed for 9LGS treated with BrUdR + TMZ and irradiated at an ultra-high dose rate.Conclusion This study demonstrated significant and synergistic, increases in cell death are achievable when BrUdR + TMZ treated cells are irradiated with ultra-high dose rate synchrotron radiation, highlighting the potential of this novel combination to treat brain cancer. Of equal significance is that co-administration of BrUdR and TMZ increased cell death with 6 MV irradiation.