Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Mechanisms of Disease: preclinical reports of antineoplastic synergistic action of bisphosphonates

Nature Clinical Practice Oncology volume 3, pages 325–338 (2006)Cite this article

Abstract

For patients with malignant bone disease, bisphosphonate therapy is the standard treatment. Preclinical and preliminary clinical data suggest that bisphosphonates have direct or indirect antitumor effects: they affect growth-factor release, cancer-cell adhesion, invasion and viability, angiogenesis, and apoptosis of cancer cells. These effects might be enhanced through co-administration with chemotherapy agents, biological agents, or both. We survey the biochemical pathways and molecular targets of bisphosphonates, and discuss the molecular mechanisms of these antitumor effects, as well as the documented antineoplastic preclinical effects of bisphosphonates used in combination with cytotoxic and biological drugs. Moreover, the positive interactions between bisphosphonates and farnesyltransferase inhibitors, KIT receptor tyrosine kinase inhibitors (e.g. imatinib mesylate) and cyclo-oxygenase-2 inhibitors are discussed in relation to their potential synergistic and additive effects. We briefly discuss identification of new molecular targets of bisphosphonates from genomic and proteomic analysis, and highlight the cellular consequences of drug-related enzyme inhibition.

Key Points

  • On the basis of the results of completed phase III trials, bisphosphonates have become the standard treatment for tumor-induced bone disease, significantly reducing the incidence of skeletal complications and having analgesic effects on bone pain

  • Zoledronic acid is the only bisphosphonate that has demonstrated significant clinical benefit not only in breast cancer patients, but also in prostate cancer, lung cancer and renal cancer

  • There are an increasing number of preclinical studies investigating the molecular rationale of combining bisphosphonates with several antineoplastic agents

  • Several in vitro studies have addressed whether bisphosphonates could act synergistically with various cytotoxic drugs, and the most convincing data for a synergistic action between bisphosphonates and cytotoxic agents were demonstrated for zoledronic acid

  • There is an urgent need to identify new molecular targets of aminobisphosphonates; genomic and proteomic studies could drive molecular research and identify suitable targets for these agents

  • In the clinic, chemotherapy and bisphosphonates are not given in any particular sequence, and treatment intervals vary; preclinical data indicate that to achieve maximum effects from the combined treatments, the sequence and the timing of drug administration have an important role and could determine the efficacy of the therapy, both in advanced disease and in the adjuvant setting

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Schematic representation of the mevalonate pathway and the effects of nitrogen-containing bisphosphonates.
Figure 2: Schematic representation of technical platforms for identification of nitrogen-containing bisphosphonates' targets.

Similar content being viewed by others

References

  1. Ferlay J et al. (2001) GLOBOCAN 2000: cancer incidence, mortality and prevalence worldwide, version 1.0. IARC CancerBase no. 5. Lyon: IARCPress [http://www-dep.iarc.fr/globocan/cdrom.htm]

  2. Coleman RE (2001) Metastatic bone disease: clinical features, pathophysiology and treatment strategies. Cancer Treat Rev 27: 165–176

    Article  CAS  PubMed  Google Scholar 

  3. Coleman RE (1997) Skeletal complications of malignancy. Cancer 80 (Suppl 8): S1588–S1594

    Article  Google Scholar 

  4. Zekri J et al. (2001) The skeletal metastatic complications of renal cell carcinoma. Int J Oncol 19: 379–382

    CAS  PubMed  Google Scholar 

  5. Ross JR et al. (2003) Systematic review of role of bisphosphonates on skeletal morbidity in metastatic cancer. BMJ 327: 469–471

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Green JR and Rogers MJ (2002) Pharmacologic profile of zoledronic acid: a highly potent inhibitor of bone resorption. Drug Dev Res 55: 210–224

    Article  CAS  Google Scholar 

  7. Theriault RL et al. (1999) Pamidronate reduces skeletal morbidity in women with advanced breast cancer and lytic bone lesions: a randomized, placebo-controlled trial. Protocol 18 Aredia Breast Cancer Study Group. J Clin Oncol 17: 846–854

    Article  CAS  PubMed  Google Scholar 

  8. Hortobagyi GN et al. (1996) Efficacy of pamidronate in reducing skeletal complications in patients with breast cancer and lytic bone metastases. Protocol 19 Aredia Breast Cancer Study Group. N Engl J Med 335: 1785–1791

    Article  CAS  PubMed  Google Scholar 

  9. Rosen LS et al. (2003) Long-term efficacy and safety of zoledronic acid compared with pamidronate disodium in the treatment of skeletal complications in patients with advanced multiple myeloma or breast carcinoma: a randomized, double-blind, multicenter, comparative trial. Cancer 98: 1735–1744

    Article  CAS  PubMed  Google Scholar 

  10. Major PP et al. (2003) Multiple event analysis of zoledronic acid trials in patients with cancer metastatic to bone. Proc Am Soc Clin Oncol 22: 762

    Google Scholar 

  11. Rosen LS et al. (2004) Zoledronic acid is superior to pamidronate for the treatment of bone metastases in breast carcinoma patients with at least one osteolytic lesion. Cancer 100: 36–43

    Article  CAS  PubMed  Google Scholar 

  12. Saad F et al. (2004) Long-term efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer. J Natl Cancer Inst 96: 879–882

    Article  CAS  PubMed  Google Scholar 

  13. Rosen LS et al. (2004) Long-term efficacy and safety of zoledronic acid in the treatment of skeletal metastases in patients with nonsmall cell lung carcinoma and other solid tumors: a randomized, phase III, double-blind, placebo-controlled trial. Cancer 100: 2613–2621

    Article  CAS  PubMed  Google Scholar 

  14. Lipton A et al. (2004) Long-term efficacy and safety of zoledronic acid in patients with bone metastases from renal cell carcinoma. In: What is new in bisphosphonates? Seventh workshop on bisphosphonates—from the laboratory to the patient: 2004 March 24–26; Davos, Switzerland. www.ibmsonline.org/cancerbone.htm

    Google Scholar 

  15. Soma MR et al. (1992) Cholesterol and mevalonic acid modulation in cell metabolism and multiplication. Toxicol Lett 64–65 Spec No: 1–15

    Article  Google Scholar 

  16. Rogers MJ (2003) New insights into the molecular mechanisms of action of bisphosphonates. Curr Pharm Des 9: 2643–2658

    Article  CAS  PubMed  Google Scholar 

  17. Rogers MJ (2004) From molds and macrophages to mevalonate: a decade of progress in understanding the molecular mode of action of bisphosphonates. Calcif Tissue Int 75: 451–461

    Article  CAS  PubMed  Google Scholar 

  18. Quilliam LA et al. (2002) A growing family of guanine nucleotide exchange factors is responsible for activation of Ras-family GTPases. Prog Nucleic Acid Res Mol Biol 71: 391–444

    Article  CAS  PubMed  Google Scholar 

  19. Matallanas D et al. (2006) Distinct utilization of effectors and biological outcomes resulting from site-specific Ras activation: Ras functions in lipid rafts and Golgi complex are dispensable for proliferation and transformation. Mol Cell Biol 26: 100–116

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Kho Y et al. (2004) A tagging-via-substrate technology for detection and proteomics of farnesylated proteins. Proc Natl Acad Sci USA 101: 12479–12484

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Reid TS et al. (2004) Crystallographic analysis of CaaX prenyltransferases complexed with substrates defines rules of protein substrate selectivity. J Mol Biol 343: 417–433

    Article  CAS  PubMed  Google Scholar 

  22. Armstrong SA et al. (1995) CAAX geranylgeranyl transferase transfers farnesyl as efficiently as geranylgeranyl to RhoB. J Biol Chem 270: 7864–7868

    Article  CAS  PubMed  Google Scholar 

  23. Lerner EC et al. (1997) Inhibition of the prenylation of K-Ras, but not H- or N-Ras, is highly resistant to CAAX peptidomimetics and requires both a farnesyltransferase and a geranylgeranyltransferase I inhibitor in human tumor cell lines. Oncogene 15: 1283–1288

    Article  CAS  PubMed  Google Scholar 

  24. Rowell CA et al. (1997) Direct demonstration of geranylgeranylation and farnesylation of Ki-Ras in vivo. J Biol Chem 272: 14093–14097

    Article  CAS  PubMed  Google Scholar 

  25. Whyte DB et al. (1997) K- and N-Ras are geranylgeranylated in cells treated with farnesyl protein transferase inhibitors. J Biol Chem 272: 14459–14464

    Article  CAS  PubMed  Google Scholar 

  26. Diel IJ et al. (1998) Reduction in new metastases in breast cancer with adjuvant clodronate treatment. N Engl J Med 339: 357–363

    Article  CAS  PubMed  Google Scholar 

  27. Powles T et al. (2002) Randomized, placebo-controlled trial of clodronate in patients with primary operable breast cancer. J Clin Oncol 20: 3219–3224

    Article  CAS  PubMed  Google Scholar 

  28. Saarto T et al. (2001) Adjuvant clodronate treatment does not reduce the frequency of skeletal metastases in node-positive breast cancer patients: 5-year results of a randomized controlled trial. J Clin Oncol 19: 10–17

    Article  CAS  PubMed  Google Scholar 

  29. Jaschke A et al. (2004) Adjuvant clodronate treatment improves the overall survival of primary breast cancer patients with micrometastases to bone marrow—a longtime follow-up. Proc Am Soc Clin Oncol 23: 9

    Google Scholar 

  30. Powles T et al. (2004) Oral clodronate for adjuvant treatment of operable breast cancer: results of a randomized, double-blind, placebo-controlled multicenter trial. Proc Am Soc Clin Oncol 23: 9

    Google Scholar 

  31. Saarto T et al. (2004) Ten-year follow-up of a randomized controlled trial of adjuvant clodronate treatment in node-positive breast cancer patients. Proc Am Soc Clin Oncol 23: 8

    Google Scholar 

  32. Green JR (2004) Bisphosphonates: preclinical review. Oncologist 9 Suppl 4: S3–S13

    Article  Google Scholar 

  33. Dieli F et al. (2003) Induction of gammadelta T-lymphocyte effector functions by bisphosphonate zoledronic acid in cancer patients in vivo. Blood 102: 2310–2311

    Article  CAS  PubMed  Google Scholar 

  34. Benford HL et al. (2001) Visualization of bisphosphonate-induced caspase-3 activity in apoptotic osteoclasts in vitro. Bone 28: 465–473

    Article  CAS  PubMed  Google Scholar 

  35. Fromigue O et al. (2000) Bisphosphonates induce breast cancer cell death in vitro. J Bone Miner Res 15: 2211–2221

    Article  CAS  PubMed  Google Scholar 

  36. Senaratne SG et al. (2002) The bisphosphonate zoledronic acid impairs Ras membrane [correction of impairs membrane] localisation and induces cytochrome c release in breast cancer cells. Br J Cancer 86: 1479–1486

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Boissier S et al. (2000) Bisphosphonates inhibit breast and prostate carcinoma cell invasion, an early event in the formation of bone metastases. Cancer Res 60: 2949–2954

    CAS  PubMed  Google Scholar 

  38. Boissier S et al. (1997) Bisphosphonates inhibit prostate and breast carcinoma cell adhesion to unmineralized and mineralized bone extracellular matrices. Cancer Res 57: 3890–3894

    CAS  PubMed  Google Scholar 

  39. van der Pluijm G et al. (1996) Bisphosphonates inhibit the adhesion of breast cancer cells to bone matrices in vitro. J Clin Invest 98: 698–705

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Pickering LM et al. (2003) Adhesion of breast cancer cells to extracellular matrices is inhibited by zoledronic acid and enhanced by aberrant Ras signalling. Proc Am Soc Clin Oncol 22: 863

    Google Scholar 

  41. Sato K et al. (2005) Cytotoxic effects of gammadelta T cells expanded ex vivo by a third generation bisphosphonate for cancer immunotherapy. Int J Cancer 116: 94–99

    Article  CAS  PubMed  Google Scholar 

  42. Wood J et al. (2002) Novel antiangiogenic effects of the bisphosphonate compound zoledronic acid. J Pharmacol Exp Ther 302: 1055–1061

    Article  CAS  PubMed  Google Scholar 

  43. Croucher PI et al. (2003) Zoledronic acid treatment of 5T2MM-bearing mice inhibits the development of myeloma bone disease: evidence for decreased osteolysis, tumor burden and angiogenesis, and increased survival. J Bone Miner Res 18: 482–492

    Article  CAS  PubMed  Google Scholar 

  44. Fournier P et al. (2002) Bisphosphonates inhibit angiogenesis in vitro and testosterone-stimulated vascular regrowth in the ventral prostate in castrated rats. Cancer Res 62: 6538–6544

    CAS  PubMed  Google Scholar 

  45. Bonjean K et al. (2001) Zoledronate modulates endothelial cell surface receptors involved in angiogenesis. Proc Am Assoc Cancer Res 42: 106

    Google Scholar 

  46. Santini D et al. (2003) Zoledronic acid induces significant and long-lasting modifications of circulating angiogenic factors in cancer patients. Clin Cancer Res 9: 2893–2897

    CAS  PubMed  Google Scholar 

  47. Santini D et al. (2002) Pamidronate induces modifications of circulating angiogenetic factors in cancer patients. Clin Cancer Res 8: 1080–1084

    CAS  PubMed  Google Scholar 

  48. Neville-Webbe HL et al. (2005) Sequence- and schedule-dependent enhancement of zoledronic acid induced apoptosis by doxorubicin in breast and prostate cancer cells. Int J Cancer 113: 364–371

    Article  CAS  PubMed  Google Scholar 

  49. Neville-Webbe HL et al. (2005) Understanding drug-sequence-dependent synergistic induction of apoptosis by zoledronic acid (ZOL) and doxorubicin (DOX) in breast cancer [abstract]. Cancer Treat Rev 31 (Suppl 1): 45 S28

    Google Scholar 

  50. Woodward J et al. (2005) The combined effects of zoledronic acid (ZOL) and doxorubicin (DOX) on breast cancer cell invasion in vitro. Anticancer Drugs 16: 845–854

    Article  CAS  PubMed  Google Scholar 

  51. Vogt U et al. (2004) Breast tumour growth inhibition in vitro through the combination of cyclophosphamide/methotrexate/5-fluorouracil, epirubicin/cyclophosphamide, epirubicin/paclitaxel, and epirubicin/docetaxel with the bisphosphonates ibandronate and zoledronic acid. Oncol Rep 12: 1109–1114

    CAS  PubMed  Google Scholar 

  52. Jagdev SP et al. (2001) The bisphosphonate, zoledronic acid, induces apoptosis of breast cancer cells: evidence for synergy with paclitaxel. Br J Cancer 84: 1126–1134

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Neville-Webbe HL et al. (2006) Mechanisms of the synergistic interaction between the bisphosphonate zoledronic acid and the chemotherapy agent paclitaxel in breast cancer cells in vitro. Tumor Biol 27: 92–103

    Article  CAS  Google Scholar 

  54. Kimura S et al. (2004) Antiproliferative efficacy of the third-generation bisphosphonate, zoledronic acid, combined with other anticancer drugs in leukemic cell lines. Int J Hematol 79: 37–43

    Article  CAS  PubMed  Google Scholar 

  55. Hiraga T et al. (2003) Effects of oral UFT combined with or without zoledronic acid on bone metastasis in the 4T1/luc mouse breast cancer. Int J Cancer 106: 973–979

    Article  CAS  PubMed  Google Scholar 

  56. Matsumoto S et al. (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

    Article  PubMed  Google Scholar 

  57. Zhou Z et al. (2005) Zoledronic acid inhibits primary bone tumor growth in Ewing sarcoma. Cancer 104: 1713–1720

    Article  CAS  PubMed  Google Scholar 

  58. Trojan J et al. (2005) In vitro chemosensitivity to gemcitabine, oxaliplatin and zoledronic acid predicts treatment response in metastatic gastric cancer. Anticancer Drugs 16: 87–91

    Article  CAS  PubMed  Google Scholar 

  59. Tassone P et al. (2000) Growth inhibition and synergistic induction of apoptosis by zoledronate and dexamethasone in human myeloma cell lines. Leukemia 14: 841–844

    Article  CAS  PubMed  Google Scholar 

  60. Magnetto S et al. (1999) Additive antitumor activities of taxoids in combination with the bisphosphonate ibandronate against invasion and adhesion of human breast carcinoma cells to bone. Int J Cancer 83: 263–269

    Article  CAS  PubMed  Google Scholar 

  61. Ullen A et al. (2003) Additive/synergistic anti-tumoral effects on prostate cancer cells in vitro following treatment with a combination of gemcitabine and zoledronic acid [abstract #1737]. Proc Am Soc Clin Oncol 22: 432

    Google Scholar 

  62. Heymann D et al. (2005) Enhanced tumor regression and tissue repair when zoledronic acid is combined with ifosfamide in rat osteosarcoma. Bone 37: 74–86

    Article  CAS  PubMed  Google Scholar 

  63. Hoskin PJ et al. (2000) Effect of local radiotherapy for bone pain on urinary markers of osteoclast activity. Lancet 355: 1428–1429

    Article  CAS  PubMed  Google Scholar 

  64. Algur E et al. (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

    Article  CAS  PubMed  Google Scholar 

  65. Kim SJ et al. (2005) Modulation of bone microenvironment with zoledronate enhances the therapeutic effects of STI571 and paclitaxel against experimental bone metastasis of human prostate cancer. Cancer Res 65: 3707–3715

    Article  CAS  PubMed  Google Scholar 

  66. Seabra MG (2001) Isoprenylcysteine carboxyl methyltransferase. In The Enzymes, edn 3 vol XXI, 131–154 (Ed. Sigman DS) San Diego: Academic Press

    Google Scholar 

  67. Gibbs JB (2001) Farnesyltransferase inhibitors. In The Enzymes, edn 3 vol XXI, 81–103 (Ed. Sigman DS) San Diego: Academic Press

    Google Scholar 

  68. Yokayama K and Gelb MH (2001) Protein geranylgeranyltransferase type I. In The Enzymes, edn 3 vol XXI, 105–130 (Ed. Sigman DS) San Diego: Academic Press

    Google Scholar 

  69. Caraglia M et al. (2004) The farnesyl transferase inhibitor R115777 (Zarnestra) synergistically enhances growth inhibition and apoptosis induced on epidermoid cancer cells by Zoledronic acid (Zometa) and Pamidronate. Oncogene 23: 6900–6913

    Article  CAS  PubMed  Google Scholar 

  70. Lee MV et al. (2001) Bisphosphonate treatment inhibits the growth of prostate cancer cells. Cancer Res 61: 2602–2608

    CAS  PubMed  Google Scholar 

  71. Andela VB et al. (2002) Synergism of aminobisphosphonates and farnesyl transferase inhibitors on tumor metastasis. Clin Orthop Relat Res 397: 228–239

    Article  Google Scholar 

  72. Druker BJ et al. (2001) Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukaemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med 344: 1038–1042

    Article  CAS  PubMed  Google Scholar 

  73. Druker BJ et al. (2001) Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 344: 1031–1037

    Article  CAS  PubMed  Google Scholar 

  74. Ottmann OG et al. (2002) A phase 2 study of imatinib in patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoid leukemias. Blood 100: 1965–1971

    Article  CAS  PubMed  Google Scholar 

  75. Gorre ME et al. (2001) Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 293: 876–880

    Article  CAS  PubMed  Google Scholar 

  76. Hofmann WK et al. (2002) Ph(+) acute lymphoblastic leukemia resistant to the tyrosine kinase inhibitor STI571 has a unique BCRABL gene mutation. Blood 99: 1860–1862

    Article  PubMed  Google Scholar 

  77. le Coutre P et al. (2000) Induction of resistance to the Abelson inhibitor STI571 in human leukemic cells through gene amplification. Blood 95: 1758–1766

    CAS  PubMed  Google Scholar 

  78. Weisberg E and Griffin JD (2000) Mechanism of resistance to the ABL tyrosine kinase inhibitor STI571 in BCR/ABL-transformed hematopoietic cell lines. Blood 95: 3498–3505

    CAS  PubMed  Google Scholar 

  79. Mahon FX et al. (2000) Selection and characterization of BCR-ABL positive cell lines with differential sensitivity to the tyrosine kinase inhibitor STI571: diverse mechanisms of resistance. Blood 96: 1070–1079

    CAS  PubMed  Google Scholar 

  80. Hoover RR et al. (2002) Overcoming STI571 resistance with the farnesyltransferase inhibitor SCH66336. Blood 100: 1068–1071

    Article  CAS  PubMed  Google Scholar 

  81. Fang JY and Richardson BC (2005) The MAPK signalling pathways and colorectal cancer. Lancet Oncol 6: 322–327

    Article  CAS  PubMed  Google Scholar 

  82. Kuroda J et al. (2003) The third-generation bisphosphonate zoledronate synergistically augments the anti-Ph+ leukemia activity of imatinib mesylate. Blood 102: 2229–2235

    Article  CAS  PubMed  Google Scholar 

  83. Witters LM et al. (2003) Effect of the combination of docetaxel, zoledronic acid, and a COX-2 inhibitor on the growth of human breast cancer cell lines. Am J Clin Oncol 26: S92–S97

    Article  PubMed  Google Scholar 

  84. Zhang PL et al. (2004) Pamidronate resistance and associated low ras levels in breast cancer cells: a role for combinatorial therapy. Ann Clin Lab Sci 34: 263–270

    CAS  PubMed  Google Scholar 

  85. Yata K et al. (2002) Synergistic growth inhibition of YM529 with biologic response modifiers (BRMs) in myeloma cells. Int J Hematol 75: 534–539

    Article  CAS  PubMed  Google Scholar 

  86. Yuasa T et al. (2005) A third-generation bisphosphonate, minodronic acid (YM529), augments the interferon alpha/beta-mediated inhibition of renal cell cancer cell growth both in vitro and in vivo. Clin Cancer Res 15: 853–859

    Google Scholar 

  87. Mocellin S et al. (2005) DNA array-based gene profiling: from surgical specimen to the molecular portrait of cancer. Ann Surg 241: 16–26

    PubMed  PubMed Central  Google Scholar 

  88. Mariadason JM et al. (2003) Microarray analysis in the clinical management of cancer. Hematol Oncol Clin North Am 17: 377–387

    Article  PubMed  Google Scholar 

  89. Pahl A (2005) Gene expression profiling using RNA extracted from whole blood: technologies and clinical applications. Expert Rev Mol Diagn 5: 43–52

    Article  CAS  PubMed  Google Scholar 

  90. Pinillos AG et al. (2005) Effects of zoledronic acid in prostate cancer cell lines: a pharmacogenomic approach [abstract #4782]. J Clin Oncol 23 (Suppl)

  91. Wulfkuhle J et al. (2004) Genomic and proteomic technologies for individualisation and improvement of cancer treatment. Eur J Cancer 40: 2623–2632

    Article  CAS  PubMed  Google Scholar 

  92. Stoeckli M et al. (2001) Imaging mass spectrometry: a new technology for the analysis of protein expression in mammalian tissues. Nat Med 7: 493–496

    Article  CAS  PubMed  Google Scholar 

  93. Emmert-Buck MR et al. (2000) An approach to proteomic analysis of human tumors. Mol Carcinog 27: 158–165

    Article  CAS  PubMed  Google Scholar 

  94. Emmert-Buck MR et al. (1996) Laser capture microdissection. Science 274: 998–1001

    Article  CAS  PubMed  Google Scholar 

  95. Chen T et al. (2002) Pharmacokinetics and pharmacodynamics of zoledronic acid in cancer patients with bone metastases. J Clin Pharmacol 42: 1228–1236

    Article  CAS  PubMed  Google Scholar 

  96. Caraglia M et al. (2006) Emerging anti-cancer molecular mechanisms of aminobisphosphonates. Endocr Relat Cancer 13: 7–26

    Article  CAS  PubMed  Google Scholar 

  97. Lennernas B et al. (2004) Antiangiogenic effect of metronomic paclitaxel treatment in prostate cancer and non-tumor tissue in the same animals: a quantitative study. APMIS 112: 201–209

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Assistant Professor in general pathology and Senior Hospital Scientist in medical oncology,

    Daniele Santini, Bruno Vincenzi & Giuseppe Tonini

  2. young university scientist,

    Daniele Santini, Bruno Vincenzi & Giuseppe Tonini

  3. Associate Professor in medical oncology and Chair of medical oncology, at University Campus Bio-Medico, Rome, Italy

    Daniele Santini, Bruno Vincenzi & Giuseppe Tonini

  4. Senior Research Fellow,

    Michele Caraglia & Alfredo Budillon

  5. Chair of the Department of Experimental Oncology, National Institute of Tumors Fondazione G Pascale, Naples, Italy

    Michele Caraglia & Alfredo Budillon

  6. Senior Lecturer in Clinical Oncology Division of Genomic Medicine, School of Medicine and Biomedical Sciences, University of Sheffield, UK

    Ingunn Holen

  7. Professor in general pathology at University La Sapienza, Rome, Italy

    Susanna Scarpa

Authors
  1. Daniele Santini
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michele Caraglia
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Bruno Vincenzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ingunn Holen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Susanna Scarpa
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Alfredo Budillon
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Giuseppe Tonini
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Daniele Santini.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Santini, D., Caraglia, M., Vincenzi, B. et al. Mechanisms of Disease: preclinical reports of antineoplastic synergistic action of bisphosphonates. Nat Rev Clin Oncol 3, 325–338 (2006). https://doi.org/10.1038/ncponc0520

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncponc0520

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing