Universität zu Köln

Schomäcker, Klaus ORCID: 0000-0003-2636-0058, Zimmermanns, Beate ORCID: 0009-0009-2207-9657, Fischer, Thomas ORCID: 0000-0001-6118-5182, Dietlein, Markus ORCID: 0000-0003-0992-6099, Sudbrock, Ferdinand, Braun, Feodor, Dietlein, Felix ORCID: 0000-0002-6651-7155, Brandenstein, Melanie von ORCID: 0000-0002-1499-7644 and Drzezga, Alexander ORCID: 0000-0001-6018-716X (2025). Overcoming Multidrug Resistance Using DNA-Localized Auger Emitters: A Comparative Analysis of Radiotoxicity in Breast Cancer Cells. International Journal of Molecular Sciences, 26 (13). MDPI. ISSN 1422-0067

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Abstract

[Artikel-Nr.: 5958] 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.

Item Type:	Article
Creators:	Creators Email ORCID ORCID Put Code Schomäcker, Klaus UNSPECIFIED https://orcid.org/0000-0003-2636-0058 UNSPECIFIED Zimmermanns, Beate UNSPECIFIED https://orcid.org/0009-0009-2207-9657 UNSPECIFIED Fischer, Thomas UNSPECIFIED https://orcid.org/0000-0001-6118-5182 UNSPECIFIED Dietlein, Markus UNSPECIFIED https://orcid.org/0000-0003-0992-6099 UNSPECIFIED Sudbrock, Ferdinand UNSPECIFIED UNSPECIFIED UNSPECIFIED Braun, Feodor UNSPECIFIED UNSPECIFIED UNSPECIFIED Dietlein, Felix UNSPECIFIED https://orcid.org/0000-0002-6651-7155 UNSPECIFIED Brandenstein, Melanie von UNSPECIFIED https://orcid.org/0000-0002-1499-7644 UNSPECIFIED Drzezga, Alexander UNSPECIFIED https://orcid.org/0000-0001-6018-716X UNSPECIFIED
URN:	urn:nbn:de:hbz:38-800051
Identification Number:	10.3390/ijms26135958
Journal or Publication Title:	International Journal of Molecular Sciences
Volume:	26
Number:	13
Number of Pages:	15
Date:	20 June 2025
Publisher:	MDPI
ISSN:	1422-0067
Language:	English
Faculty:	Faculty of Medicine
Divisions:	Außeruniversitäre Forschungseinrichtungen > Forschungszentrum Jülich Faculty of Medicine > Nuklearmedizin > Klinik und Poliklinik für Nuklearmedizin Faculty of Medicine > Urologie > Klinik und Poliklinik für Urologie
Subjects:	Medical sciences Medicine
['eprint_fieldname_oa_funders' not defined]:	Publikationsfonds UzK
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/80005