The aim of this study was to investigate the effect of inhibiting a v b 3 /a v b 5 integrins by cilengitide in experimentally induced breast cancer bone metastases using noninvasive imaging techniques. For this purpose, nude rats bearing established breast cancer bone metastases were treated with cilengitide, a small molecule inhibitor of a v b 3 and a v b 5 integrins (75 mg/kg, five days per week; n 5 12 rats) and compared to vehicle-treated control rats (n 5 12). In a longitudinal study, conventional magnetic resonance imaging (MRI) and flat panel volumetric computed tomography were used to assess the volume of the soft tissue tumor and osteolysis, respectively, and dynamic contrast-enhanced (DCE-) MRI was performed to determine functional parameters of the tumor vasculature reflecting blood volume and blood vessel permeability. In rats treated with cilengitide, VCT and MRI showed that osteolytic lesions and the respective bone metastatic soft tissue tumors progressed more slowly than in vehicle-treated controls. DCE-MRI indicated a decrease in blood volume and an increase in vessel permeability and immunohistology revealed increased numbers of immature vessels in cilengitide-treated rats compared to vehicle controls. In conclusion, treatment of experimental breast cancer bone metastases with cilengitide resulted in pronounced antiresorptive and antitumor effects, suggesting that a v b 3 /a v b 5 inhibition may be a promising therapeutic approach for bone metastases.Bone metastases occur frequently in many human malignancies including breast, prostate and lung carcinoma. The stimulation of osteoclasts by tumor cells proliferating within the bone marrow is a feature of the pathogenesis of bone metastases, and both the tumor and the bone microenvironment must be considered when strategies for therapy of bone metastases are developed.1 Bisphosphonates are potent inhibitors of osteoclast function that have been used over the last decades to treat patients with bone metastases. However, they do not induce regression of bone metastases. This, together with the adverse effects associated with bisphosphonate therapy such as osteonecrosis of the jaw and renal toxicity, emphasize the urgent need for the development of novel therapies that can be applied alternatively and as combination partners to target bone metastases more effectively.Integrins are a family of 24 transmembrane proteins that integrate extracellular and intracellular activities. Besides their role in promoting physical adhesion, integrin signaling can induce cell spreading, migration, survival, proliferation and differentiation.2 The a v b 3 integrin interacts with several extracellular matrix (ECM) proteins including vitronectin, fibronectin, osteopontin, bone sialoprotein (BSP) and fibrinogen. 3,4 It is strongly expressed on activated tumor endothelial cells, whereas on resting endothelial cells in nondiseased tissues, its expression is generally low. [5][6][7] In the pathogenesis of bone metastases, osteoclasts too express a v b 3 integrin, and selec...