Dose-Dependent Growth Delay Of Breast Cancer Xenografts In The Bone Marrow Of Mice Treated With Ra-223: The Role Of Bystander Effects And Their Potential For Therapy

The role of radiation-induced bystander effects in radiation therapy remains unclear. With renewed interest in therapy with alpha-particle emitters, and their potential for sterilizing disseminated tumor cells (DTCs), it is critical to determine the contribution of bystander effects to the overall response so they can be leveraged for maximum clinical benefit. Methods: Female Foxn1(nu) athymic nude mice were administered 0, 50, or 600 kBq/kg (RaCl2)-Ra-223 to create bystander conditions. At 24 hours after administration, MDA-MB-231 or MCF-7 human breast cancer cells expressing luciferase were injected into the tibial marrow compartment. Tumor burden was tracked weekly via bioluminescence. Results: The MDA-MB-231 xenografts were observed to have a 10-day growth delay in the 600 kBq/kg treatment group only. In contrast, MCF-7 cells had 7-and 65-day growth delays in the 50 and 600 kBq/kg groups, respectively. Histologic imaging of the tibial marrow compartment, alpha-camera imaging, and Monte Carlo dosimetry modeling revealed DTCs both within and beyond the range of the alpha-particles emitted from Ra-223 in bone for both MCF-7 and MDA-MB-231 cells. Conclusion: Taken together, these results support the participation of Ra-22(3)-induced antiproliferative/cytotoxic bystander effects in delayed growth of DTC xenografts. They indicate that the delay depends on the injected activity and therefore is dose-dependent. They suggest using (RaCl2)-Ra-223 as an adjuvant treatment for select patients at early stages of breast cancer.