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DNA double strand breaks as predictor of efficacy of the alpha-particle emitter Ac-225 and the electron emitter Lu-177 for somatostatin receptor targeted radiotherapy.
Open accessAbstract
RATIONALE: Key biologic effects of the alpha-particle emitter Actinium-225 in comparison to the beta-particle emitter Lutetium-177 labeled somatostatin-analogue DOTATOC in vitro and in vivo were studied to evaluate the significance of γH2AX-foci formation. METHODS: To determine the relative biological effectiveness (RBE) between the two isotopes (as - biological consequence of different ionisation-densities along a particle-track), somatostatin expressing AR42J cells were incubated with Ac-225-DOTATOC and Lu-177-DOTATOC up to 48 h and viability was analyzed using the MTT assay. DNA double strand breaks (DSB) were quantified by immunofluorescence staining of γH2AX-foci. Cell cycle was analyzed by flow cytometry. In vivo uptake of both radiolabeled somatostatin-analogues into subcutaneously growing AR42J tumors and the number of cells displaying γH2AX-foci were measured. Therapeutic efficacy was assayed by monitoring tumor growth after treatment with activities estimated from in vitro cytotoxicity. RESULTS: Ac-225-DOTATOC resulted in ED50 values of 14 kBq/ml after 48 h, whereas Lu-177-DOTATOC displayed ED50 values of 10 MBq/ml. The number of DSB grew with increasing concentration of Ac-225-DOTATOC and similarly with Lu-177-DOTATOC when applying a factor of 700-fold higher activity compared to Ac-225. Already 24 h after incubation with 2.5-10 kBq/ml, Ac-225-DOTATOC cell-cycle studies showed up to a 60% increase in the percentage of tumor cells in G2/M phase. After 72 h an apoptotic subG1 peak was also detectable. Tumor uptake for both radio peptides at 48 h was identical (7.5%ID/g), though the overall number of cells with γH2AX-foci was higher in tumors treated with 48 kBq Ac-225-DOTATOC compared to tumors treated with 30 MBq Lu-177-DOTATOC (35% vs. 21%). Tumors with a volume of 0.34 ml reached delayed exponential tumor growth after 25 days (44 kBq Ac-225-DOTATOC) and after 21 days (34 MBq Lu-177-DOTATOC). CONCLUSION: γH2AX-foci formation, triggered by beta- and alpha-irradiation, is an early key parameter in predicting response to internal radiotherapy.
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“225Ac and 177Lu triggered-γH2AX-foci formation is an early key parameter in predicting response to internal radiotherapy.”
From Alpha-peptide receptor radionuclide therapy using actinium-225 labeled somatostatin receptor agonists and antagonists (2022) · cites this paper as [156]
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Metadata
- Authors
- Graf, F., Fahrer, J., Maus, S., Morgenstern, A., Bruchertseifer, F., Venkatachalam, S., Fottner, C., Weber, M. M., Huelsenbeck, J., Schreckenberger, M., Kaina, B., & Miederer, M.
- Affiliations
- University Medical Center of the Johannes Gutenberg University Mainz (DE)
- European Commission (BE)
- Corresponding author
- Miederer, Matthias
- ORCID
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2014-02-07
- Volume
- 9
- Issue
- 2
- Pages
- e88239
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3917860
- OpenAlex
- W1984398166
- Cited by
- 143
- References
- 33
- Citations by year
- 2026: 7 · 2025: 13 · 2024: 18 · 2023: 19 · 2022: 12 · 2021: 17 · 2020: 12 · 2019: 16 · 2018: 15 · 2017: 5 · 2016: 5 · 2015: 3 · 2014: 1
- FWCI
- 3.65
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Gutenberg Open Science (submittedVersion, cc-by-nd)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Joint Research Centre (European Commission) (submittedVersion)
- Gutenberg Open Science (cc-by)
- Funders
- Bundesministerium für Bildung und Forschung
- Topics
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Radiopharmaceutical Chemistry and Applications
- Health Sciences › Medicine › Oncology › Neuroendocrine Tumor Research Advances
- Physical Sciences › Physics and Astronomy › Radiation › Radiation Therapy and Dosimetry
- Keywords
- actinium-225, lutetium-177, somatostatin receptors, targeted radiotherapy, alpha-emitting radionuclides, DNA double-strand breaks, γH2AX foci, relative biological effectiveness, DOTATOC, AR42J cells, tumor cell cycle, apoptosis, tumor uptake, treatment efficacy, somatostatin analogues
- MeSH terms
- Actinium, Alpha Particles, Animals, Cell Cycle, Lutetium, Radioisotopes, Cell Death, Receptors, Somatostatin, Neuroendocrine Tumors, Cell Line, Tumor, Rats, DNA Breaks, Double-Stranded
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