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

Multidrug resistance (MDR) represents a major obstacle to successful chemotherapy and, due to overlapping defense mechanisms, such as enhanced DNA repair and the evasion of apoptosis, can also be associated with radioresistance. In this study, we investigated whether MDR breast cancer cells (MCF-7/CMF) exhibit reduced susceptibility to radiation-induced DNA fragmentation compared to their non-resistant parental counterpart (MCF-7). Using a nucleosome-based ELISA, we quantified the chromatin fragmentation in MCF-7 and MCF-7/CMF cells following their exposure to four radiopharmaceuticals: [^99mTc]pertechnetate, [¹³¹I]NaI (sodium iodide), [¹²⁵I]NaI, and the DNA-incorporating compound [¹²⁵I]iododeoxyuridine ([¹²⁵I]IdU). Each radioactive preparation was assessed across a range of activity concentrations, using a two-way ANOVA. For [^99mTc]pertechnetate and [¹³¹I]NaI, significantly higher DNA fragmentation was observed in the sensitive cell line, whereas [¹²⁵I]NaI showed no significant difference between the two phenotypes. In contrast to the other radiopharmaceuticals, [¹²⁵I]IdU induced greater fragmentation in resistant cells. This finding was supported by the statistical analysis (a 63.7% increase) and visualized in the corresponding dose-response plots. These results highlight the critical role of the intranuclear enrichment of Auger emitters and support further development of radiopharmaceuticals in accordance with this principle. Our data suggest that radiotoxicity is governed not by linear energy transfer (LET) alone, but, fundamentally, by the spatial proximity of the radionuclide to the DNA. Targeting tumor cell DNA with precision radiotherapeutics may, therefore, offer a rational strategy to overcome MDR in breast cancer.