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
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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
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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
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There are an increasing number of preclinical studies investigating the molecular rationale of combining bisphosphonates with several antineoplastic agents
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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
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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
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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
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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
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DOI: https://doi.org/10.1038/ncponc0520
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