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Bisphosphonates: Preclinical Review JONATHAN R. GREEN Novartis Pharma AG, Basel, Switzerland Key Words. Bisphosphonates · Zoledronic acid · Bone resorption · Apoptosis · Antitumor effects · Mevalonate pathway ABSTRACT Bisphosphonates effectively inhibit osteoclast-medi- ated bone resorption and are integral in the treatment of benign and malignant bone diseases. The evolution of bis- phosphonates over the past 30 years has led to the devel- opment of nitrogen-containing bisphosphonates (N-BPs), which have a mechanism of action different from that of the nonnitrogen-containing bisphosphonates. Studies conducted over the past decade have elucidated the mechanism of action and pharmacologic properties of the N-BPs. N-BPs exert their effects on osteoclasts and tumor cells by inhibiting a key enzyme in the mevalonate path- way, farnesyl diphosphate synthase, thus preventing pro- tein prenylation and activation of intracellular signaling proteins such as Ras. Recent evidence suggests that N-BPs also induce production of a unique adenosine triphosphate analogue (Apppi) that can directly induce apoptosis. Our increased understanding of the pharma- cologic effects of bisphosphonates is shedding light on the mechanisms by which they exert antitumor effects. As a result of their biochemical effects on protein prenylation, N-BPs induce caspase-dependent apoptosis, inhibit matrix metalloproteinase activity, and downregulate αvβ3 and αvβ5 integrins. In addition, zoledronic acid (Zometa ? ; Novartis Pharmaceuticals Corp.; East Hanover, NJ and Basel, Switzerland) exerts synergistic antitumor activity when combined with other anticancer agents. Zoledronic acid also inhibits tumor cell adhesion to the extracellular matrix and invasion through Matrigel? and has antiangiogenic activity. A growing body of evidence from animal models demonstrates that zoledronic acid and other bisphosphonates can reduce skeletal tumor burden and prevent metastasis to bone. Further studies are needed to