Conference Presentation (After Call)

FZJ-2017-06720

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Enhanced cyto- and genotoxic effects of Auger electron emitter-labeled DNA-Triplex-forming oligonucleotides in vitro

Dahmen, V.FZJ* ; Reiter, S. ; Pomplun, E. ; Kriehuber, R. (Corresponding author)FZJ*

2014

Please use a persistent id in citations: http://hdl.handle.net/2128/15657

Abstract: The efficacy of DNA-targeting radionuclide therapies might be strongly enhanced by employing short range particleemitter.However, the therapeutic use of radionuclides requests a thorough radiation dosimetry especially whenshort-range particles are released. In this study we compared the ß-emitter P-32 and the Auger electron emitter I-125in terms of biological effectiveness per decay and per unit dose when located in the close proximity to the DNA byusing Triplex-forming oligonucleotides (TFO).TFO bind to the DNA double helix in a sequence specific manner. Therefore, TFO seem to be a suitable carrier forradionuclides emitting short-range electrons to damage exclusively targeted DNA sequences. We investigatedclonogenicity (colony-forming assay; CFA) in the human squamous carcinoma cell line II (SCL-II) and the induction ofDNA double strand breaks (DSB; 53BP1 foci assay) after exposure with P-32 or I-125 labeled TFO for differentnumbers of accumulated decays. The employed TFO targeted a specific DNA sequence located in the glyceraldehyde3-phosphate dehydrogenase (GAPDH) gene.Results: I-125-labeled TFO binding to single targets were shown to induce a pronounced decrease in cell survival andan increase of DSB with increasing numbers of accumulated decays per cell. The reduction in cell survival asmeasured in the CFA reached the D37 value at ~ 350 accumulated decays per cell, equivalent to ~ 1.2 Gy cellnucleus dose. Using the same TFO but labeled with P-32 revealed neither a significant decrease of the survivalfraction nor an increase of the DSB rate in SCL-II cells up to ~ 4,000 accumulated decays per cell which is equivalentto ~ 1 Gy cell nucleus dose.Summary & Conclusions: The reduction of cell survival and the increase of DNA damage proved to be much morepronounced in I-125-TFO transfected cells than observed after exposure with the P-32-labeled TFO per decay and perdose unit. This can be explained by the high number of low energy Auger electrons emitted by I-125 per decay,leading to a high ionization density in the immediate vicinity of the decay site, probably producing very complex DNAlesions, overcharging the cellular DNA-repair mechanisms.

Keyword(s): Biology (2nd)

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Contributing Institute(s):

1. Sicherheit und Strahlenschutz, Umgebungsüberwachung,Strahlenbiologie (S-US)

Research Program(s):

1. 899 - ohne Topic (POF3-899) (POF3-899)

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Database coverage:

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