Abstract
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.
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References
Langer C, Hirsh V (2010) Skeletal morbidity in lung cancer patients with bone metastases: demonstrating the need for early diagnosis and treatment with bisphosphonates. Lung Cancer 67:4–11
Ricciardi S, Marinis F (2009) Treatment of bone metastases in lung cancer: the actual role of zoledronic acid. Rev Recent Clin Trials 4(3):205–211
Guise T (2008) Antitumor effects of bisphosphonates: promising preclinical evidence. Cancer Treat Rev 34:S19–S24
Winter MC, Holen I, Coleman RE (2008) Exploring the anti-tumor activity of bisphosphonates in early breast cancer. Cancer Treat Rev 34:453–475
Jimenez-Soriano Y, Bagan JV (2005) Bisphosphonates, as a new cause of drug-induced jaw osteonecrosis: an update. Med Oral Patol Oral Cir Bucal 10(Suppl 2):E88–E91
Morgan G, Lipton A (2010) Antitumor effects and anticancer applications of bisphosphonates. Semin Oncol 37:S30–S40
Soulafa A, Almazrooa BDS, Sook-Bin W (2009) Bisphosphonate and nonbisphosphonate-associated osteonecrosis of the jaw: a review. JADA 140:864–875
Neville-Webbe HL, Coleman RE (2010) Bisphosphonates and RANK ligand inhibitors for the treatment and prevention of metastatic bone disease. Eur J Cancer 46:1211–1222
Coleman RE (2009) Adjuvant bisphosphonates in breast cancer: are we witnessing the emergence of a new therapeutic strategy? Eur J Cancer 4(5):1909–1915
Algur E, Macklis RM, Hafeli UO (2005) Synergistic cytotoxic effects of zoledronic acid and radiation in human prostate cancer and myeloma cell lines. Int J Radiat Oncol Biol Phys 61:535–542
Ural AU, Avcu F, Candir M et al (2006) In vitro synergistic cytoreductive effects of zoledronic acid and radiation on breast cancer cells. Breast Cancer Res 8:1–7
Matsumoto S, Kimura S, Segawa H, Kuroda J, Yuasa T, Sato K, Nogawa M, Tanaka F, Maekawa T, Wada H (2005) Efficacy of the third-generation bisphosphonate, zoledronic acid alone and combined with anti-cancer agents against small cell lung cancer cell lines. Lung Cancer 47:31–39
Carmichael J, DeGraff WG, Gazdar AF, Minna JD, Mitchell JB (1987) Evaluation of a tetrazolium-based semiautomated colorimetric assay: assessment of chemosensitivity testing. Cancer Res 47:936–942
Carmichael J, DeGraff WG, Gazdar AF, Minna JO, Mitchell JB (1987) Evaluation of a tetrazolium-based semiautomated colorimetric assay: assessment of radiosensitivity. Cancer Res 47:943–946
Alley MC, Scudiero OA, Monks A, Hursey ML, Czerwinski MJ, Fine DL, Abbott BJ, Mayo JG, Shoemaker RH, Boyd MR (1988) Feasibility of drug screening with panels of human tumor cell lines using a microculture tetrazolium assay. Cancer Res 48:589–601
Vicente JR, Ortega VV, Jordana MC (1997) Valor del ensayo colorimétrico con MTT en el estudio de crecimiento y citotoxicidad in vitro de líneas de melanoma. Patologia 30:18–27
Fenech M (2007) Cytokinesis block micronucleus cytome assay. Nat Protoc 5:1084–1104
International Atomic Energy Agency (2011) Cytogenetic dosimetry: applications in preparedness for and response to radiation emergencies. IAEA, Vienna
Alcaraz M, Armero D, Martínez-Beneyto Y, Castillo J, Benavente-Garcia O, Fernandez H, Alcaraz-Saura M, Canteras M (2011) Chemical genoprotection: reducing biological damage to as low as reasonably achievable levels. Dentomaxillofac Radiol 40:310–314
Sarma L, Kesavan PC (1993) Protective effects of vitamina C and E against γ-ray-induced chromosomal damage in mouse. Int J Radiat Biol 63:759–764
Ural AU, Avcu F (2005) Radiosensitizing effect of zoledronic acid in small cell lung cancer. Lung Cancer 50:271–272 (letter)
Hall EJ (1978) Radiobiology for the radiobiologist, 2nd edn. Harper do Row publishers, Philadelphia
Milas L, Hunter NR, Mason KA, Kurdoglu B, Peters LJ (1994) Enhancement of tumor radioresponse of a murine mammary carcinoma by paclitaxel. Cancer Res 54:3506–3510
Karabut AB, Gul Karabut E, Kiram TR, Ocak SG, Out O et al (2010) Oxidant and antioxidant activity in rabbit livers treated with zoledronic acid. Transplant Proc 9:3820–3822
Uchiyama M, Mihara M (1978) Determination of malonaldehyde precursor in tissues by thiobarbituric acid test. Anal Biochem 34:271
Cortas NK, Wakid WN (1990) Determination of inorganic nitrate in serum and urine by a kinetic cadmium-reduction method. Clin Chem 36:1440
Geldof AA, Slotman B (1996) Radiosensitizing effect of cisplatin in prostate cancer cell lines. Cancer Lett 101:233–239
Dewin L (1987) Combined treatment of radiation and cisdiamminedichoropltinum (II): a review of experimental and clinical data. Int J Rad Oncol Biol Phys 13:403–426
Alcaraz M, Acevedo C, Castillo J, Benavente-García O, Armero D, Vicente V et al (2009) Liposoluble antioxidants provide an effective radioprotective barrier. Br J Radiol 82:605–609
Suzuki M, Amano M, Chori J, Park HJ, Williams BW, Ono K, Song CW (2006) Synergistic effects of radiation and beta-lapachone in DU-147 human prostate cancer cells in vitro. Radiat Res 165:525–531
Acknowledgments
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).
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The authors declare that they have no conflict of interest.
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Alcaraz, M., Olivares, A., Armero, D. et al. Zoledronic acid and radiation: toxicity, synergy or radiosensitization?. Clin Transl Oncol 15, 300–306 (2013). https://doi.org/10.1007/s12094-012-0917-9
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DOI: https://doi.org/10.1007/s12094-012-0917-9