Radium 223-mediated zonal cytotoxicity of prostate cancer in bone
Menée à l'aide d'un modèle murin de métastases osseuses ayant pour origine un cancer de la prostate et menée à l'aide d'une simulation, cette étude analyse, du point de vue de la croissance tumorale et du taux d'éradication, l'efficacité d'une radiothérapie par radium-223 en fonction de la taille des lésions métastatiques et de l'étendue de la zone ciblée
Background : Bone-targeting radiotherapy with Radium-223 (Rad-223), a radioisotope emitting genotoxic alpha-radiation with limited tissue penetrance (∼100 µm), prolongs the survival of patients with metastatic prostate cancer (PCa). Confoundingly, the clinical response to Rad-223 is often followed by detrimental relapse and progression, and whether Rad-223 causes tumor-cell directed cytotoxicity in vivo remains unclear. We hypothesized that limited radiation penetrance in situ defines outcome. Methods : We tested Rad-223 overall response by PC3 and C4-2B human PCa cell lines in mouse bones (n = 5-18 tibiae/group). Rad-223 efficacy at subcellular resolution was determined by intravital microscopy analysis of dual-color fluorescent PC3 cells (n = 3-4 mice/group) in tissue-engineered bone constructs. In vivo data were fed into an in silico model to predict Rad-223 effectiveness in lesions of different sizes (1-27,306 initial cells; n = 10-100 simulations) and the predictions validated in vivo by treating PCa tumors of varying sizes in bones (n = 10-14 tibiae/group). Statistical tests were performed by two-tailed Student’s t-test or by one-way ANOVA followed by Tukey's post-hoc test. Results : Rad-223 (385 kBq/kg) delayed the growth (means ± SD; comparison with control treated mice) of PC3 (6.7 x 105 ± 4.2 x 105 vs. 2.8 x 106 ± 2.2 x 106, p = 0.01) and C4-2B tumors in bone (7.7 x 105 ± 4.0 x 105 vs. 3.5 x 106 ± 1.3 x 106, p < 0.001). Cancer cell lethality in response to Rad-223 (385 kBq/kg) was profound but zonally confined along the bone interface compared to the more distant tumor core, which remained unperturbed (day 4; 13.1 ± 2.3% apoptotic cells, 0-100 µm distance from bone vs. 3.6 ± 0.2%, >300 µm distance; p = 0.01). In silico simulations predicted greater efficacy of Rad-223 on single-cell lesions (eradication rate: 88.0%) and minimal effects on larger tumors (no eradication, 16.2% growth reduction in tumors of 27,306 cells), further confirmed in vivo for PC3 and C4-2B tumors. Conclusions : Micro-tumors showed severe growth delay or eradication in response to Rad-223, whereas macro-tumors persisted and expanded. The relative inefficacy in controlling large tumors points to application of Rad-223 in secondary prevention of early bone-metastatic disease and regimens co-targeting the tumor core.