Molecular and preclinical models enhancing anti-tumour activity of zoledronic acid

Zoledronic acid (ZOL) is an aminobisphosphonate able to inhibit the prenylation of intracellular proteins through the inhibition of farnesylpyrophosphate synthase. Prenylation is essential for the maintenance of the activation of components of signal transduction pathways regulating apoptosis and proliferation such as Ras and Ras-related proteins. ZOL has demonstrated a direct anti-tumour effect in vitro and in preclinical models, and its ability in preventing skeletal-related events is proven in patients with bone metastases from different origins. Clinical evidence on its direct anti-proliferative effects is emerging. We describe several strategies in order to improve the anti-tumour activity of ZOL. In detail, we illustrate new combinations between ZOL and cytotoxic drugs or other biological agents such as the farnesyltransferase inhibitor tipifarnib focusing on the sequence of administration of these drugs. Moreover, the efforts to find new molecular targets of ZOL through the use of technological platforms such as DNA microarrays are described.