University of Aberdeen and Aberdeen Royal Infirmary
Anti-tumour effects of bisphosphonates in multiple myeloma
At the University of Aberdeen we have coupled the expertise of the Bisphosphonate Research Group and the clinical haematologists in the Aberdeen Royal Infirmary to investigate the potential anti-tumour activity of bisphosphonates in the treatment of multiple myeloma.
Bisphosphonate drugs, such as pamidronate, are potent anti-resorptive agents effective in the treatment of osteolytic bone disease and hypercalcaemia associated with myeloma. Recent studies have shown that, in addition to their anti-resorptive effect, bisphosphonates can cause apoptosis of myeloma cells in vitro and may also increase survival of certain myeloma patients.
Hence, bisphosphonates may have direct or indirect anti-tumour effects on myeloma tumour cells within the bone micro-environment, which might explain the potential survival benefit previously described in some myeloma patients receiving pamidronate therapy.
Our in vitro studies, with myeloma cell lines and authentic human bone marrow cells from myeloma patients, suggest that pamidronate and zoledronic acid, a more potent nitrogen-containing bisphosphonate than pamidronate, cause apoptosis of myeloma cells by inhibiting the mevalonate pathway, resulting in loss of isoprenylated small GTPase proteins necessary for cell survival. The exact signalling pathways involved are the focus of current studies. To determine whether pamidronate can cause apoptosis of myeloma cells in patients, we have also begun to quantitate changes in the level of myeloma cell apoptosis in bone marrow aspirates of patients before and after pamidronate treatment.
The ultimate aim of this research is to further our understanding of the full therapeutic potential of bisphosphonates, and clarify some of the cellular and molecular interactions within the myeloma bone microenvironment in the hope of elucidating novel therapeutic targets. Our studies so far have important implications for the further development of more potent nitrogen-containing bisphosphonates, such as zoledronic acid, which may possibly have even greater anti-tumour potential in the treatment of patients with multiple myeloma.
Contact details
Dr Mike RogersDr Sharon Gordon