Overcoming Multidrug Resistance Using DNA-Localized Auger Emitters: A Comparative Analysis of Radiotoxicity in Breast...

Area of Science:

• Nuclear medicine
• Oncology
• Radiopharmaceutical therapy

Background:

• Multidrug resistance (MDR) in cancer impedes chemotherapy and can confer radioresistance.
• Overlapping defense mechanisms in MDR cells, including enhanced DNA repair and apoptosis evasion, contribute to treatment failure.
• Investigating differential responses to radiopharmaceuticals is crucial for overcoming MDR.

Purpose of the Study:

• To compare the susceptibility of multidrug resistant (MDR) breast cancer cells (MCF-7/CMF) to radiation-induced DNA fragmentation versus their sensitive counterparts (MCF-7).
• To evaluate the efficacy of different radiopharmaceuticals ([99mTc]pertechnetate, [131I]NaI, [125I]NaI, [125I]IdU) in inducing DNA damage in MDR and sensitive cells.
• To explore the role of radionuclide localization and Auger electron emission in overcoming MDR.

Main Methods:

• Quantification of chromatin fragmentation using a nucleosome-based ELISA in MCF-7 and MCF-7/CMF cell lines.
• Exposure of cells to varying concentrations of four radiopharmaceuticals: [99mTc]pertechnetate, [131I]NaI, [125I]NaI, and [125I]iododeoxyuridine ([125I]IdU).
• Statistical analysis using two-way ANOVA to determine significant differences in DNA fragmentation between cell lines and radiopharmaceuticals.

Main Results:

• Sensitive MCF-7 cells exhibited significantly higher DNA fragmentation with [99mTc]pertechnetate and [131I]NaI compared to resistant MCF-7/CMF cells.
• [125I]NaI showed no significant difference in DNA fragmentation between the two cell lines.
• The DNA-incorporating Auger emitter [125I]IdU induced significantly greater DNA fragmentation (63.7% increase) in MDR MCF-7/CMF cells compared to sensitive cells.

Conclusions:

• Radiotoxicity is influenced by the spatial proximity of the radionuclide to DNA, not solely by linear energy transfer (LET).
• Intranuclear enrichment of Auger emitters is critical for overcoming MDR in breast cancer.
• Targeting tumor cell DNA with precision radiotherapeutics, particularly Auger emitters, presents a rational strategy to overcome multidrug resistance.