Abstract
Low-energy X-rays induce Auger cascades by photoelectric absorption in iodine present in the DNA of cells labeled with 5-iodo-2’-deoxyuridine (IUdR). This photoactivation therapy results in enhanced cellular sensitivity to radiation which reaches its maximum with 50 keV photons. Synchrotron core facilities are the only way to generate such monochromatic beams. However, these structures are not adapted for the routine treatment of patients. In this study, we generated two beams emitting photon energy means of 42 and 50 keV respectively, from a conventional 225 kV X-ray source. Viability assays performed after pre-exposure to 10 μM of IUdR for 48h suggest that complex lethal damage is generated after low energy photons irradiation compared to 137Cs irradiation (662KeV). To further decipher the molecular mechanisms leading to IUdR-mediated radiosensitization, we analyzed the content of DNA damage-induced foci in two glioblastoma cell lines and showed that the decrease in survival under these conditions was correlated with an increase in the content of DNA damage-induced foci in cell lines. Moreover, the follow-up of repair kinetics of the induced double-strand breaks showed the maximum delay in cells labeled with IUdR and exposed to X-ray irradiation. Thus, there appears to be a direct relationship between the reduction of radiation survival parameters and the production of DNA damage with impaired repair of these breaks. These results further support the clinical potential use of a halogenated pyrimidine analog combined with low-energy X-ray therapy.
Highlights
Radiation therapy is a cornerstone of cancer management
Since synchrotron core facilities are not adapted for the routine treatment of patients, we aimed to produce a pseudo-monochromatic photon beam with mean energies close to the maximum dose enhancement ratio applying specific filtration on a conventional polychromatic X-ray beam
We focused on sensitization enhancement ratios at the survival fraction at 2 Gy (SF2) level (SERSF2) and at the 10% survival level (SER10), which correspond to the ratio of the SF2 or the D10 for cells without IUdR compared to those with IUdR
Summary
Most patients who overcome cancer are cured by a loco-regional treatment, in which radiotherapy plays a prominent role. One third of patient fatalities are linked to loco-regional relapses, indicating that it is absolutely necessary to increase the antitumor efficacy of radiotherapy for these patients. A decline in treatment-associated side effects (without compromising antitumor efficacy) is needed for patients who are cured by radiotherapy. Strategies to overcome such limitations include methods which allow individual cancer cells to be targeted with precise radiation dose deposition, and one way to achieve this is to combine radiation therapy with chemical compounds. Many of them have been used as radiation sensitizers to increase the therapeutic index of radiotherapy [1]. Molecules labeled with high-Z atoms such as halogenated pyrimidines, platinium salts or gadolinium texaphyrin, have been or are currently being tested in clinical trials [2,3,4,5,6,7,8]
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