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Turku, Finland

Strube A.,Bayer AG | Suominen M.I.,Pharmatest Services | Rissanen J.P.,Pharmatest Services | Mumberg D.,Bayer AG | And 3 more authors.
Osteoporosis International | Year: 2011

Sagopilone, a fully synthetic epothilone and very potent anti-tumor agent, has proved to be efficient in inhibiting bone destruction and tumor burden in a mouse model of breast cancer bone metastasis. In addition to its antiproliferative effects, this study shows direct effects of sagopilone on bone resorption and osteoclast activity. Introduction: Sagopilone, a novel fully synthetic third-generation epothilone, has proved to be efficient in inhibiting bone destruction and tumor burden in a mouse model of breast cancer bone metastasis. The aim of this study was to investigate whether the effect was primarily due to sagopilones antiproliferative effect and consequent inhibition of tumor cell growth, or if sagopilone exerts direct effects on bone resorption and osteoclast activity. Methods: Sagopilone was studied and compared to paclitaxel in vitro in human osteoclast differentiation and activity cultures. For studying the potential of sagopilone for inhibiting bone resorption in vivo, a mouse model of ovariectomy (ovx)-induced osteoporosis was utilized. Results: Sagopilone inhibited osteoclast differentiation and activity more efficiently than paclitaxel and showed less cytotoxicity. Whereas sagopilone showed inhibitory effects on human osteoclast differentiation and activity already at 5 and 15 nM, respectively, paclitaxel started to show effects only at 20 and 100 nM concentrations, respectively. Sagopilone treatment increased BMD In the mouse ovx model even though a non-optimized dose was used which is effective in tumor-bearing mice. Conclusion: This is the first study to evaluate sagopilones effects on bone resorption in non-cancerous situation. The evidence that sagopilone is beneficial for bone will strengthen the status of sagopilone as an anti-cancer compound compared to other microtubule stabilizing agents. © 2010 International Osteoporosis Foundation and National Osteoporosis Foundation. Source

Childs C.E.,University of Reading | Childs C.E.,University of Southampton | Roytio H.,DuPont Company | Roytio H.,University of Turku | And 12 more authors.
British Journal of Nutrition | Year: 2014

Prebiotics, probiotics and synbiotics are dietary ingredients with the potential to influence health and mucosal and systemic immune function by altering the composition of the gut microbiota. In the present study, a candidate prebiotic (xylo-oligosaccharide, XOS, 8 g/d), probiotic (Bifidobacterium animalis subsp. lactis Bi-07, 109 colony-forming units (CFU)/d) or synbiotic (8 g XOS+109 CFU Bi-07/d) was given to healthy adults (25-65 years) for 21 d. The aim was to identify the effect of the supplements on bowel habits, self-reported mood, composition of the gut microbiota, blood lipid concentrations and immune function. XOS supplementation increased mean bowel movements per d (P=0·009), but did not alter the symptoms of bloating, abdominal pain or flatulence or the incidence of any reported adverse events compared with maltodextrin supplementation. XOS supplementation significantly increased participant-reported vitality (P=0·003) and happiness (P=0·034). Lowest reported use of analgesics was observed during the XOS+Bi-07 supplementation period (P=0·004). XOS supplementation significantly increased faecal bifidobacterial counts (P=0·008) and fasting plasma HDL concentrations (P=0·005). Bi-07 supplementation significantly increased faecal B. lactis content (P=0·007), lowered lipopolysaccharide-stimulated IL-4 secretion in whole-blood cultures (P=0·035) and salivary IgA content (P=0·040) and increased IL-6 secretion (P=0·009). XOS supplementation resulted in lower expression of CD16/56 on natural killer T cells (P=0·027) and lower IL-10 secretion (P=0·049), while XOS and Bi-07 supplementation reduced the expression of CD19 on B cells (XOS × Bi-07, P=0·009). The present study demonstrates that XOS induce bifidogenesis, improve aspects of the plasma lipid profile and modulate the markers of immune function in healthy adults. The provision of XOS+Bi-07 as a synbiotic may confer further benefits due to the discrete effects of Bi-07 on the gut microbiota and markers of immune function. © The Authors 2014. Source

Suominen M.I.,Pharmatest Services
Journal of the National Cancer Institute | Year: 2013

Bone metastases are associated with increased morbidity and poor prognosis in breast cancer patients. Radium-223 dichloride is a calcium mimetic that localizes to bone, providing targeted therapy for skeletal metastasis. We investigated the mode of action of radium-223 dichloride using breast cancer cell, osteoclast, and osteoblast cultures as well as a mouse model of breast cancer bone metastasis. A single dose of radium-223 dichloride was used in three different settings mimicking the prevention or treatment of bone metastasis. Disease progression was monitored using fluorescence and radiographic imaging and histological analyses. The effect of radium-223 dichloride alone and in combination with doxorubicin or zoledronic acid on survival of mice was analyzed by Kaplan-Meier methods. All statistical tests used were two-sided. Radium-223 dichloride incorporated into bone matrix and inhibited proliferation of breast cancer cells and differentiation of osteoblasts and osteoclasts (all P values < .001) in vitro. In an established bone metastasis setting, radium-223 dichloride prevented tumor-induced cachexia (0/14 vs 7/14 control mice) and decreased osteolysis by 56% and tumor growth by 43% (all P values < .05). Radium-223 dichloride induced double-strand DNA breaks in cancer cells in vivo. Finally, radium-223 dichloride extended survival as a monotherapy (29.2 days, 95% confidence interval [CI] = 26.6 to 31.8 days, P = .039) and in combination with zoledronic acid (31.4 days, 95% CI = 28.8 to 34.0 days, P = .004) or doxorubicin (31.5 days, 95% CI = 29.5 to 33.5 days, P < .001) compared to the vehicle group (24.9 days, 95% CI = 23.4 to 26.4 days). Similar but even more pronounced effects were observed when radium-223 dichloride was administered in a preventive or micrometastatic setting. Our findings strongly support the development of radium-223 dichloride for the treatment of breast cancer patients with or at high risk of developing bone metastases. Source

Bjorklund M.,Danisco | Bjorklund M.,Abo Akademi University | Ouwehand A.C.,Danisco | Forssten S.D.,Danisco | And 4 more authors.
Age | Year: 2012

Ageing changes gut microbiota composition and alters immune system function. Probiotics, prebiotics and synbiotics may improve the health status of elderly individuals by modifying the intestinal environment and the microbiota composition, and by stimulating the immune system. In this work, we studied the effects of synbiotic supplementation on the gut microbiota of healthy elderly volunteers. Fifty-one elders were randomly assigned to consume either a synbiotic dietary supplement or a placebo in addition to their usual diet for a 2-week period. The synbiotic product consisted of the probiotic Lactobacillus acidophilus NCFM and the prebiotic lactitol and was ingested twice a day, with a total daily dose of 10 g lactitol and 2×1010 cells of probiotic bacteria. Before, during and after the intervention period fecal quantities of six phylogenetic bacterial groups were determined using quantitative PCR, and relative changes in total microbiota composition were assessed by percent guanineplus- cytosine profiling. The microbiota profiles showed certain relative changes within the microbial community, and indicated an increase of bifidobacteria levels during synbiotic supplementation. Quantification by PCR confirmed the in changes in the microbiota composition; for example increases in total levels of endogenous bifidobacteria and lactobacilli were recorded. Throughout the 6-week study period there was a decrease unrelated to intervention in the Blautia coccoides-Eubacterium rectale bacterial group levels and Clostridium cluster XIVab levels, but this decrease appeared to be halted during the synbiotic intervention. In conclusion, putatively beneficial changes in microbiota were observed in the elderly subjects supplemented with the synbiotic product. © The Author(s) 2011. Source

Tuomela J.,University of Turku | Tuomela J.,Pharmatest Services | Forsback S.,University of Turku | Haavisto L.,University of Turku | And 5 more authors.
EJNMMI Research | Year: 2013

Background: An unknown location hampers removal of pancreatic tumours. We studied the effects of enzyme inhibitors on the uptake of 6-[18F]fluoro-L-3,4-dihydroxyphenylalanine ([18F]FDOPA) in the pancreas, aiming at improved imaging of pancreatic adenocarcinoma. Methods: Mice bearing orthotopic BxPC3 pancreatic adenocarcinoma were injected with 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) and scanned with positron emission tomography/computed tomography (PET/CT). For [18F] FDOPA studies, tumour-bearing mice and sham-operated controls were pretreated with enzyme inhibitors of aromatic amino acid decarboxylase (AADC), catechol-O-methyl transferase (COMT), monoamine oxidase A (MAO-A) or a combination of COMT and MAO-A. Mice were injected with [18F]FDOPA and scanned with PET/CT. The absolute [18F]FDOPA uptake was determined from selected tissues using a gamma counter. The intratumoural biodistribution of [18F]FDOPA was recorded by autoradiography. The main [18F]FDOPA metabolites present in the pancreata were determined with radio-high-performance liquid chromatography. Results: [18F]FDG uptake was high in pancreatic tumours, while [18F]FDOPA uptake was highest in the healthy pancreas and significantly lower in tumours. [18F]FDOPA uptake in the pancreas was lowest with vehicle pretreatment and highest with pretreatment with the inhibitor of AADC. When mice received COMT + MAO-A inhibitors, the uptake was high in the healthy pancreas but low in the tumour-bearing pancreas. Conclusions: Combined use of [18F]FDG and [18F]FDOPA is suitable for imaging pancreatic tumours. Unequal pancreatic uptake after the employed enzyme inhibitors is due to the blockade of metabolism and therefore increased availability of [18F]FDOPA metabolites, in which uptake differs from that of [18F]FDOPA. Pretreatment with COMT + MAO-A inhibitors improved the differentiation of pancreas from the surrounding tissue and healthy pancreas from tumour. Similar advantage was not achieved using AADC enzyme inhibitor, carbidopa. © 2013 Tuomela et al. Source

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