Purpose Radium-223 dichloride (radium-223, Xofigo®), a targeted alpha therapy, is currently used for the treatment of patients with castration-resistant prostate cancer (CRPC) with bone metastases. This study examines the mode-of-action and antitumor efficacy of radium-223 in two prostate cancer xenograft models. Experimental Design Mice bearing intratibial LNCaP or LuCaP 58 tumors were randomized to groups (n = 12–17) based on lesion grade and/or serum PSA level and administered with radium-223 (300 kBq/kg) or vehicle, twice at 4-week intervals. X-rays and serum samples were obtained biweekly. Soft tissue tumors were observed macroscopically at sacrifice. Tibiae were analyzed by gamma counter, micro-CT, autoradiography and histology. Results Radium-223 inhibited tumor-induced osteoblastic bone growth and protected normal bone architecture leading to reduced bone volume in LNCaP and abiraterone-resistant LuCaP 58 models. Furthermore, radium-223 resulted in lower PSA values and reduced total tissue and tumor areas, indicating that treatment constrains prostate cancer growth in bone. In addition, radium-223 suppressed abnormal bone metabolic activity as evidenced by decreased number of osteoblasts and osteoclasts and reduced level of the bone formation marker PINP. Mode-of-action studies revealed that radium-223 was deposited in the intratumoral bone matrix. DNA double-strand breaks were induced in cancer cells within 24 hours after radium-223 treatment and PSA levels were significantly lower 72 hours post treatment providing further evidence of the anti-tumor effects. Conclusion Taken together, radium-223 therapy exhibits a dual targeting mode-of-action that induces tumor cell death and suppresses tumor-induced pathological bone formation in tumor microenvironment in osseous CRPC growth in mice.

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, 10 9 colony-forming units (CFU)/d) or synbiotic (8 g XOS þ 10 9 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 (P¼0·009), 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 (P¼0·003) and happiness (P¼ 0·034). Lowest reported use of analgesics was observed during the XOS þ Bi-07 supplementation period (P¼0·004). XOS supplementation significantly increased faecal bifidobacterial counts (P¼ 0·008) and fasting plasma HDL concentrations (P¼0·005). Bi-07 supplementation significantly increased faecal B. lactis content (P¼ 0·007), lowered lipopolysaccharide-stimulated IL-4 secretion in whole-blood cultures (P¼0·035) and salivary IgA content (P¼ 0·040) and increased IL-6 secretion (P¼ 0·009). XOS supplementation resulted in lower expression of CD16/56 on natural killer T cells (P¼ 0·027) and lower IL-10 secretion (P¼ 0·049), while XOS and Bi-07 supplementation reduced the expression of CD19 on B cells (XOS £ Bi-07, P¼0·009). 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 þ 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.

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.