Radium-223-Induced Bystander Effects Cause DNA Damage and Apoptosis in Disseminated Tumor Cells in Bone Marrow

Area of Science:

• Radiobiology
• Oncology
• Radiopharmaceuticals

Background:

• Radiation-induced bystander effects (RIBE) are hypothesized to contribute to the efficacy of radiopharmaceuticals.
• Radium-223 dichloride (²²³RaCl₂) is an alpha-emitting radiopharmaceutical used in cancer therapy.
• Understanding RIBE is crucial for optimizing ²²³RaCl₂ treatment and expanding its clinical applications.

Purpose of the Study:

• To quantify biological changes, including DNA damage and apoptosis, in disseminated tumor cells (DTC) and osteocytes due to direct radiation and bystander effects from ²²³RaCl₂.
• To elucidate the role of RIBE in the growth delay of DTC induced by ²²³RaCl₂.
• To inform the clinical use of alpha-particle emitting radiopharmaceuticals.

Main Methods:

• Human breast cancer cells (MDA-MB-231 or MCF-7) were inoculated into nude mice.
• Mice received intravenous injections of 50 or 600 kBq/kg ²²³RaCl₂.
• Tibiae were harvested at 1 and 3 days post-inoculation to assess DNA damage (γ-H2AX foci) and apoptosis in cancer cells and osteocytes.

Main Results:

• Both irradiated and bystander cancer cells exhibited DNA damage.
• Bystander MDA-MB-231 cells showed DNA damage at both ²²³RaCl₂ doses, while bystander MCF-7 cells required the higher dose.
• Osteocytes displayed DNA damage irrespective of the cancer cell line, and bystander MDA-MB-231 cells and osteocytes showed increased apoptosis.

Conclusions:

• Radiation-induced bystander effects play a significant role in the cytotoxicity of ²²³RaCl₂ against disseminated tumor cells.
• These findings support further clinical investigation into the efficacy of ²²³RaCl₂ for preventing breast cancer DTC progression.
• RIBE contribute to the overall anti-tumor effect of alpha-particle emitting radiopharmaceuticals.