Advertisement

Clinical and Translational Oncology

, Volume 15, Issue 4, pp 300–306 | Cite as

Zoledronic acid and radiation: toxicity, synergy or radiosensitization?

  • M. AlcarazEmail author
  • A. Olivares
  • D. Armero
  • M. Alcaraz-Saura
  • D. Achel
Research Article

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.

Keywords

Radiosensitivity Zoledronic acid Synergism Radiation effects Bisphosphonates 

Notes

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).

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    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 67:4–11PubMedCrossRefGoogle Scholar
  2. 2.
    Ricciardi S, Marinis F (2009) Treatment of bone metastases in lung cancer: the actual role of zoledronic acid. Rev Recent Clin Trials 4(3):205–211PubMedCrossRefGoogle Scholar
  3. 3.
    Guise T (2008) Antitumor effects of bisphosphonates: promising preclinical evidence. Cancer Treat Rev 34:S19–S24PubMedCrossRefGoogle Scholar
  4. 4.
    Winter MC, Holen I, Coleman RE (2008) Exploring the anti-tumor activity of bisphosphonates in early breast cancer. Cancer Treat Rev 34:453–475PubMedCrossRefGoogle Scholar
  5. 5.
    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–E91PubMedGoogle Scholar
  6. 6.
    Morgan G, Lipton A (2010) Antitumor effects and anticancer applications of bisphosphonates. Semin Oncol 37:S30–S40PubMedCrossRefGoogle Scholar
  7. 7.
    Soulafa A, Almazrooa BDS, Sook-Bin W (2009) Bisphosphonate and nonbisphosphonate-associated osteonecrosis of the jaw: a review. JADA 140:864–875Google Scholar
  8. 8.
    Neville-Webbe HL, Coleman RE (2010) Bisphosphonates and RANK ligand inhibitors for the treatment and prevention of metastatic bone disease. Eur J Cancer 46:1211–1222PubMedCrossRefGoogle Scholar
  9. 9.
    Coleman RE (2009) Adjuvant bisphosphonates in breast cancer: are we witnessing the emergence of a new therapeutic strategy? Eur J Cancer 4(5):1909–1915CrossRefGoogle Scholar
  10. 10.
    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 61:535–542PubMedCrossRefGoogle Scholar
  11. 11.
    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 8:1–7CrossRefGoogle Scholar
  12. 12.
    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 47:31–39PubMedCrossRefGoogle Scholar
  13. 13.
    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 47:936–942PubMedGoogle Scholar
  14. 14.
    Carmichael J, DeGraff WG, Gazdar AF, Minna JO, Mitchell JB (1987) Evaluation of a tetrazolium-based semiautomated colorimetric assay: assessment of radiosensitivity. Cancer Res 47:943–946PubMedGoogle Scholar
  15. 15.
    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 48:589–601PubMedGoogle Scholar
  16. 16.
    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 30:18–27Google Scholar
  17. 17.
    Fenech M (2007) Cytokinesis block micronucleus cytome assay. Nat Protoc 5:1084–1104CrossRefGoogle Scholar
  18. 18.
    International Atomic Energy Agency (2011) Cytogenetic dosimetry: applications in preparedness for and response to radiation emergencies. IAEA, ViennaGoogle Scholar
  19. 19.
    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 40:310–314PubMedCrossRefGoogle Scholar
  20. 20.
    Sarma L, Kesavan PC (1993) Protective effects of vitamina C and E against γ-ray-induced chromosomal damage in mouse. Int J Radiat Biol 63:759–764PubMedCrossRefGoogle Scholar
  21. 21.
    Ural AU, Avcu F (2005) Radiosensitizing effect of zoledronic acid in small cell lung cancer. Lung Cancer 50:271–272 (letter)PubMedCrossRefGoogle Scholar
  22. 22.
    Hall EJ (1978) Radiobiology for the radiobiologist, 2nd edn. Harper do Row publishers, PhiladelphiaGoogle Scholar
  23. 23.
    Milas L, Hunter NR, Mason KA, Kurdoglu B, Peters LJ (1994) Enhancement of tumor radioresponse of a murine mammary carcinoma by paclitaxel. Cancer Res 54:3506–3510PubMedGoogle Scholar
  24. 24.
    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 9:3820–3822CrossRefGoogle Scholar
  25. 25.
    Uchiyama M, Mihara M (1978) Determination of malonaldehyde precursor in tissues by thiobarbituric acid test. Anal Biochem 34:271CrossRefGoogle Scholar
  26. 26.
    Cortas NK, Wakid WN (1990) Determination of inorganic nitrate in serum and urine by a kinetic cadmium-reduction method. Clin Chem 36:1440PubMedGoogle Scholar
  27. 27.
    Geldof AA, Slotman B (1996) Radiosensitizing effect of cisplatin in prostate cancer cell lines. Cancer Lett 101:233–239PubMedCrossRefGoogle Scholar
  28. 28.
    Dewin L (1987) Combined treatment of radiation and cisdiamminedichoropltinum (II): a review of experimental and clinical data. Int J Rad Oncol Biol Phys 13:403–426CrossRefGoogle Scholar
  29. 29.
    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 82:605–609PubMedCrossRefGoogle Scholar
  30. 30.
    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 165:525–531PubMedCrossRefGoogle Scholar

Copyright information

© Federación de Sociedades Españolas de Oncología (FESEO) 2012

Authors and Affiliations

  • M. Alcaraz
    • 1
    Email author
  • A. Olivares
    • 1
  • D. Armero
    • 2
  • M. Alcaraz-Saura
    • 1
  • D. Achel
    • 3
  1. 1.Radiology and Physical Medicine Department, Faculty of Medicine/DentistryUniversity of MurciaMurciaSpain
  2. 2.Nursing Department, Faculty of NursingUniversity of MurciaMurciaSpain
  3. 3.Applied Radiation Biology CentreRadiological and Medical Sciences Research Institute, Ghana Atomic Energy CommissionLegon-AccraGhana

Personalised recommendations