Bisphosphonates prevent loss of bone mass and are used to treat postmenopausal osteoporosis and also to reduce bone loss in metastatic disease in cancer patients. Bisphosphonates can be divided into two sub-classes, those that do not contain nitrogen such as etidronic acid, and those that do contain nitrogen such as zoledronic acid.
Bisphosphonates that do not contain nitrogen interfere with ATP-linked energy metabolism in osteoclasts whereas the activity of nitrogenous bisphosphonates is related to their ability to inhibit farnesyl diphosphate synthase (FPPS) a key enzyme in the HMG-CoA reductase (mevalonate) pathway. Farnesyl diphosphate (FPP) is used for the post-translational prenylation of small GTPases such as Ras, and depletion of FPP is thought to be the primary mechanism for inhibition of osteoclast function. The anticancer activity of nitrogenous bisphosphonates has also been attributed to inhibition of FPPS and results from recent clinical trials in oestrogen-receptor positive breast cancer and hormone-refractory prostate cancer have been very encouraging. The transition states involved in FPP biosynthesis by FPPS are expected to be broadly similar to those of other prenyltranferases and inhibition of geranylgeranyl diphosphate synthase (GGPPS) has been suggested to be more important than inhibition of FPPS for the anti-cancer activity of bisphosphonates.
An international team led by Professor Eric Oldfield at the University of Illinois set out to design compounds that would inhibit both FPPS and GGPPS but have lower affinity for bone tissue and so be more effective in reaching other tissues. Writing in the Journal of the American Chemical Society, they describe potent inhibitors of FPPS and GGPPS that are effective in blocking tumour cell growth and invasiveness, both in vitro and in vivo. One of the compounds, BPH-715, is about 200 times more active in killing tumour cells than zoledronic acid and, since it is more lipophilic, has a lower affinity for bone. Studies showed that although BPH-175 binds to both FPPS and GGPPS, it inhibits GGPPS more strongly.
As well as inhibiting FPPS and GGPPS, bisphosphonates such as zoledronic acid and BPH-715 also stimulate γδ T-cells which help to kill tumour cells.
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