Figure 5. Radium-223 is deposited in the intratumoral bone matrix and induces DNA double-strand breaks in tumor cells, osteoblasts and osteoclasts in LuCaP 58 mouse model of prostate cancer growth in bone.

A, Autoradiography analysis of undecalcified tissue sections was used to define the localization of radium-223 particles (black dots) in osteoblastic/mixed bone metastasis. Analysis was done at 24 h after single intravenous administration of radium-223 (300 kBq/kg). Green arrows indicate radium-223 deposition in the proximity of osteoblasts and blue arrows point radium-223 deposits within the tumor bed. Scale bar = 100 μm; 200x magnification. B, Total activity of healthy and contralateral tumor-bearing tibias of mice treated with single dose of radium-223 measured with a gamma counter (cpm, counts per minute; n = 11–12). C, Relative serum PSA 72 h after radium-223 dosing (% of value on day 0; mean ± SD, n = 11–12, p = 0.04926). D, Relative necrotic tumor area in animals sacrificed 24, 48, or 72 h after a single dose of radium-223 and 72 h after vehicle dosing (n = 4–5, p = 0.27134). E, γ-H2AX positive tumor cells (n/microscope field). The animals were sacrificed 24, 48, or 72 h after a single radium-223 dose and 72 h after vehicle dosing (n = 4–5; p = 0.00297, 0.03665 and 0.00714 for 24h, 48h and 72 h, respectively. F, γ-H2AX positive osteoblasts (% of all osteoblasts). The animals were sacrificed 24, 48, or 72 h after a single radium-223 dose and 72 h after vehicle dosing (n = 3–5; p = 0.03148 for 72h). G, γ-H2AX positive osteoclasts (% of all osteoclasts). The animals were sacrificed 24, 48, or 72 h after a single radium-223 dose and 72 h after vehicle dosing (n = 4–5; p = 0.00714 for 72h). In box plots, horizontal lines show 5^th, 25^th, 50^th, 75^th and 95^th centiles and crosses indicate mean values. ns = not significant,* p<0.05, ** p<0.01, *** p<0.001.