Radiosensitisation enhancement effect of BrUdR and Ta ₂ O ₅ NSPs in combination with 5-Fluorouracil antimetabolite in kilovoltage and megavoltage radiation

Abstract

This article demonstrates in vitro a synergistic effect on 9L gliosarcoma cells when exposed to bromodeoxyuridine (BrUdR) and a low concentration (100 times lower than the IC50) of 5-Fluorouracil (5-FU), in combination with x-ray irradiation. The synergy is brought about by several important factors including the x-ray beam energy, atomic number of the BrUdR (Z=35), effectiveness of 5-FU in reducing the available repair processes and distribution of the BrUdR in and around the 9L cells (32% of the total substitution of BrUdR for thymidine into nucleus DNA). Our results show that the synergistic effect, evident in an optimised 125 kVp x-ray field, leads to a radiosensitisation enhancement ratio at the 10% survival level (SER 10% ) of 2.11. We highlight the importance of the aforementioned factors by similarly performed experiments for higher Z (Z=73) tantalum pentoxide nano-structured particles (Ta 2 O 5 NSPs) that are substituted for the BrUdR in larger concentration (∼10 times). In the Ta 2 O 5 NSPs experiments, no synergistic effect is observed in the kVp irradiation with optimal energy spectrum even though the effective Z and NSP concentration is much higher than for BrUdR. All experiments were repeated using a MV x-ray irradiation field and no synergistic effect is observed for either the BrUdR or Ta 2 O 5 case. We therefore hypothesise that the synergistic outcome is due to more drastic and complex damages induced by BrUdR under the exposure of kVp radiation. Such damages are achieved by the localisation of the BrUdR in the DNA and the high LET (very short range) secondary electrons in combination with the 5-FU. In order to achieve similar synergistic effects in the more clinically relevant x-ray energy field the concentration of the high Z material needs to be greater in order to create a higher LET electron environment.

Effect of resveratrol on the radiosensitivity of 5‐FU in human breast cancer MCF‐7 cells

“…5‐FU, a chemotherapeutic agent has been using as a treatment for a variety of tumor types nowadays, both alone and in combination with other drugs. Researchers confirmed that 5‐FU can sensitize the cells to ionizing radiation that is depended directly with the level of halogenated pyrimidine that incorporated into DNA (in vitro and in vivo studies). Although the molecular mechanisms of 5‐FU radiosensitization are not clear it is assumed that 5‐FU sensitizes cells through enhancing the formation of double‐strand break .…”

“…Hence, more and more attention of researchers has been attracted to radiosensitizers, which lower the radiation dose‐response threshold for cancer cells without increasing the normal tissue radiosensitivity . To obtain this result the most effective approach is to use halogenated pyrimidines, 5‐fluorouracil (5‐FU) . 5‐FU is commonly used as an anticancer drug for cancer cells, which can be used with X‐ray.…”

“…10 To obtain this result the most effective approach is to use halogenated pyrimidines, 5-fluorouracil (5-FU). 11 5-FU is commonly used as an anticancer drug for cancer cells, 12 which can be used with X-ray. 5-FU is a metabolic analog of uracil and thymine in RNA and DNA synthesis respectively.…”

Thulium oxide nanoparticles as radioenhancers for the treatment of metastatic cutaneous squamous cell carcinoma

“…These nanoparticles exhibit preferential absorption of kilovoltage (or low) energy x-rays due to high photoelectric cross section of the nanoparticle relative to low Z atoms (C, H, N, O etc) in tissues resulting in superior tumor cell treatment and normal tissue sparing (Retif et al 2015, Liu et al 2018. Nanoparticle radiosensitisation of megavoltage x-rays has also been documented (Mcdonald et al 2018) and was attributed to underlying differences in the dose-enhancement on the nanoscale (Mcmahon et al 2011) or due to increasing radiochemical activity in the cellular environment (Guerreiro et al 2019).…”