RESUMEN
INTRODUCTION: 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. OBJECTIVES: 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). RESULTS: 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 %). CONCLUSION: 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.
Asunto(s)
Difosfonatos/farmacología , Imidazoles/farmacología , Tolerancia a Radiación/efectos de los fármacos , Fármacos Sensibilizantes a Radiaciones/farmacología , Fármacos Sensibilizantes a Radiaciones/uso terapéutico , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/efectos de la radiación , Células Cultivadas , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Linfocitos/efectos de los fármacos , Linfocitos/fisiología , Linfocitos/efectos de la radiación , Pruebas de Micronúcleos , Dosis de Radiación , Factores de Tiempo , Ácido ZoledrónicoRESUMEN
PURPOSE: To compare the genoprotective and radioprotective effect of carnosol (COL) against damage induced by ionizing radiation with similar effects produced by different antioxidant compounds. METHODS: The genoprotective effect was studied by means of the micronucleus test for antimutagenic activity in which the reduction in the frequency of micronuclei was evaluated in cytokinesis-blocked cells of human lymphocytes. The radioprotective effects were studied by cell viability test (MTT) in PNT2 (normal prostate) and B16F10 (melanoma) cell lines when they were administered before exposure to different X-ray doses (4, 6, 8, 10 and 0 Gy). RESULTS: Carnosol shows a significant genoprotective capacity (p < 0.001) against radiation with a protection factor of 50 %, and a dose-reduction factor of 4.3. Cell survival obtained with COL administered before exposure to 10 Gy of X-rays showed a protection factor of 55.1 %, eliminating 39 % of radiation-induced cell death in normal epithelial cells of prostate (PNT2) (p < 0.001). However, in the melanoma cell lines (B16F10) assayed, COL acted not as a radioprotector, but as a sensitizing agent increasing the cellular death by 34 % (p < 0.01) and producing an enhancement ratio of 2.12. CONCLUSIONS: Carnosol may be developed as a radioprotective agent in the non-tumoral cells. However, in the B10F16 melanoma cells, melanogenesis is activated by COL leading to redistribution of the enzymatic balances of glutathione and cysteine-lyase production, which could compromise the intracellular redox defence system. This effect appears as an increase in the capacity of ionizing radiation-induced damage, and thus exhibits a paradoxical protective effect of COL on melanoma cells.