Mechanisms of disease: Preclinical reports of antineoplastic synergistic action of bisphosphonates.

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.