Zoledronic acid and radiation: toxicity, synergy or radiosensitization?
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Zoledronic acid (Z) is a bisphosphonate used in hypercalcaemia-related cancer, in complications for bone metastasis and in postmenopausal osteoporosis and it has been related to osteoradionecrosis, especially when associated with radiation to the head and neck structures.
To determine the radiosensitization capacity of zoledronic acid in the combined treatment with ionizing radiation (IR) by evaluating its genotoxic and cytotoxic capacities in non-tumoral cells.
Materials and methods
The genotoxic effect of Z was studied by means of the micronucleus test in cytokinesis-blocked cells of human lymphocytes irradiated before and after a 2 Gy irradiation, while the cytotoxic effect was studied by a cell viability test in the PNT2 cell line before and after exposure to different X-ray doses (0–20 Gy) in four groups (Z alone, radiation alone, Z + IR and IR + Z).
A dose-dependent and time-dependent cytotoxic effect of Z and IR on PNT2 cells in vitro (p > 0.001) was demonstrated. With the concentrations recommended for humans, the combined treatment had a more pronounced effect than individual treatments (p < 0.001). The effect was synergic (CI < 1), increasing the Z enhancement ratio (2.6) and sensitization factor (56 %); the effect of Z was always greater after IR exposure. In the genotoxic effect, only the administration of Z after irradiation (IR + Z) increased chromosome damage (p < 0.001) and the sensibilization factor (35.7 %).
High concentrations of Z are toxic, but the concentrations recommended for clinical practice in humans give it the characteristics of a radiosensitization agent, whose effect is even greater when administered after IR.
KeywordsRadiosensitivity Zoledronic acid Synergism Radiation effects Bisphosphonates
This report was supported by a grant from the National Spanish R&D Programme CENIT of the Spanish Ministry of Science and Technology denominated SENIFOOD. A. Olivares was able to take part in this study because of a grant from the Seneca Foundation (Coordination Research Centre of the Region of Murcia, Spain), and D. Achel thanks to an International Atomic Energy Agency (IAEA) sponsored fellowship (GHA10021).
Conflict of interest
The authors declare that they have no conflict of interest.
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