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Cited by 143Radiopharmaceutical Chemistry and ApplicationsNeuroendocrine Tumor Research AdvancesRadiation Therapy and Dosimetry

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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.

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Graf, Franziska, Fahrer, Jörg, Maus, Stephan, Morgenstern, Alfred, Bruchertseifer, Frank, Venkatachalam, Senthil, Fottner, Christian, Weber, Matthias M., Huelsenbeck, Johannes, Schreckenberger, Mathias, Kaina, Bernd, Miederer, Matthias·2014·PLoS ONE
DOI 10.1371/journal.pone.0088239PMC PMC3917860
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Abstract

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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Crossref · 10.1371/journal.pone.0088239

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Figures

Figure 1 DNA damage response in AR42J cells following ionizing irradiation. (A) and (B) Cells were irradiated with 5 Gy and time-dependent DNA damage response was assessed over 24 h using western blot analysis.
Figure 1 DNA damage response in AR42J cells following ionizing irradiation. (A) and (B) Cells were irradiated with 5 Gy and time-dependent DNA damage response was assessed over 24 h using western blot analysis.CC BY · PubMed Central
Figure 2 Viability of AR42J cells at 48225Ac-DOTATOC (A) and 177Lu-DOTATOC (B).
Figure 2 Viability of AR42J cells at 48225Ac-DOTATOC (A) and 177Lu-DOTATOC (B).CC BY · PubMed Central
Figure 3 Number of γH2AX foci in AR42J cells at 24 and 48 h after incubation with 225Ac-DOTATOC (left) and 177Lu-DOTATOC (right). (A) shows representative images from all activity levels, (B) shows quantification of γH2AX foci and (C) shows two representative examples for pan nuclear staining after high dose 225Ac-DOTATOC treatment.
Figure 3 Number of γH2AX foci in AR42J cells at 24 and 48 h after incubation with 225Ac-DOTATOC (left) and 177Lu-DOTATOC (right). (A) shows representative images from all activity levels, (B) shows quantification of γH2AX foci and (C) shows two representative examples for pan nuclear staining after high dose 225Ac-DOTATOC treatment.CC BY · PubMed Central
Figure 4 Comparison of cell viability and the number of γH2AX foci in AR42J cells at 48 h after incubation with 225Ac-DOTATOC and 177Lu-DOTATOC.
Figure 4 Comparison of cell viability and the number of γH2AX foci in AR42J cells at 48 h after incubation with 225Ac-DOTATOC and 177Lu-DOTATOC.CC BY · PubMed Central
Figure 5 Single-cell gel electrophoresis (alkaline comet assay) of AR42J cells at 24 h and 48 h after incubation with 225Ac-DOTATOC (A) and 177Lu-DOTATOC (B). DNA damage was calculated by the tail moment, the most frequent used parameter of comet features. SubG1 fraction of AR42J cells at 48 and 72 h after incubation with 225Ac-DOTATOC (C) and 177Lu-DOTATOC (D).
Figure 5 Single-cell gel electrophoresis (alkaline comet assay) of AR42J cells at 24 h and 48 h after incubation with 225Ac-DOTATOC (A) and 177Lu-DOTATOC (B). DNA damage was calculated by the tail moment, the most frequent used parameter of comet features. SubG1 fraction of AR42J cells at 48 and 72 h after incubation with 225Ac-DOTATOC (C) and 177Lu-DOTATOC (D).CC BY · PubMed Central
Figure 6 Cell-cycle distribution of AR42J cells at 48 h after incubation with 225Ac-DOTATOC (left) and 177Lu-DOTATOC (right) (SD <15%).
Figure 6 Cell-cycle distribution of AR42J cells at 48 h after incubation with 225Ac-DOTATOC (left) and 177Lu-DOTATOC (right) (SD <15%).CC BY · PubMed Central
Figure 7 Immunofluorescence staining of DNA double strand breaks (γH2AX) in AR42J tumors after treatment with 47 kBq 225Ac-DOTATOC, 30 MBq of 177Lu-DOTATOC, 1 µg DOTATOC (unlabelled), or PBS. (A) Representative images, (B) and quantification of γH2AX- positive cells. Scale bar (white) corresponds to 25 µm. (C) Growth delay after treatment with equitoxic doses of 225Ac-DOTATOC (n = 3, 44kBq/mouse) and 177Lu-DOTATOC (n = 4, 34 MBq/mouse) versus untreated control (n = 4).
Figure 7 Immunofluorescence staining of DNA double strand breaks (γH2AX) in AR42J tumors after treatment with 47 kBq 225Ac-DOTATOC, 30 MBq of 177Lu-DOTATOC, 1 µg DOTATOC (unlabelled), or PBS. (A) Representative images, (B) and quantification of γH2AX- positive cells. Scale bar (white) corresponds to 25 µm. (C) Growth delay after treatment with equitoxic doses of 225Ac-DOTATOC (n = 3, 44kBq/mouse) and 177Lu-DOTATOC (n = 4, 34 MBq/mouse) versus untreated control (n = 4).CC BY · PubMed Central

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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)
DOI
10.1371/journal.pone.0088239
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
Licence
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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