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    Keywords: ANGIOGENESIS ; GROWTH ; TUMOR-CELLS ; IN-VIVO ; THERAPY ; GENE ; breast cancer ; PROSTATE-CANCER ; CANCER-CELLS ; INTEGRIN ; PERMEABILITY ; INTEGRINS ; F-18-FDG PET ; BONE METASTASES ; BREAST-CANCER CELLS ; ALPHA-V-BETA-3 ; RAT MODEL ; gene expression analysis ; Cilengitide ; THERAPEUTIC OPPORTUNITIES
    Abstract: Aim of this study was to investigate the specific treatment effects of inhibiting alpha v beta 3/alpha v beta 5 integrins by cilengitide in an animal model of breast cancer bone metastases using dynamic F-18-FDG PET and gene expression analysis. For this purpose, nude rats bearing bone metastases were treated with cilengitide, a small molecule inhibitor of alpha v beta 3 and alpha v beta 5 integrins, from day 30 to 55 after tumor cell inoculation of MDA-MB-231 breast cancer cells (25 mg/kg, 5 days per week; n = 8 rats) and compared to control rats (n = 8). Dynamic F-18-FDG PET data were assessed at days 30, 35 and 55 after tumor cell inoculation determining the vascular fraction VB and the metabolic variables k1-k4. At day 55, genome-wide mRNA expression analysis was performed to assess the treatment-specific expression changes from cilengitide-treated and control rats. In a longitudinal F-18-FDG PET study, the vascular fraction VB was significantly decreased in bone metastases between days 30/35, 30/55 and 35/55, whereas the kinetic parameters k1 and k4 were significantly decreased between days 30/55 in skeletal lesions of treated animals. Gene expression analysis from bone metastases at day 55 revealed that tumor-produced integrins (alpha v beta 5) as well as factors relevant for angiogenesis (alpha v beta 3, VEGF, PDGF), bone resorption (PTHrP and RANKL), extracellular matrix remodeling (collagen, CD44) and bone marrow microenvironment (CXCR4) were significantly reduced upon therapy with cilengitide. Here, we provide evidence that cilengitide inhibits pivotal factors of all compartments of bone metastases including tumor cells, vasculature and bone microenvironment in vivo and by whole-genome transcriptome analysis
    Type of Publication: Journal article published
    PubMed ID: 23229276
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