Please use this identifier to cite or link to this item: doi:10.22028/D291-41354
Title: Dual Nucleosomal Double-Strand Breaks Are the Key Effectors of Curative Radiation Therapy
Author(s): Brahme, Anders
Lorat, Yvonne
Language: English
Title: Biophysica
Volume: 3
Issue: 4
Pages: 668-694
Publisher/Platform: MDPI
Year of Publication: 2023
Free key words: dual double-strand breaks
dual nucleosomal DSB repair
DSB imaging
TP53 damage sensors and modification sites
light ion radiation therapy
therapy optimization
multiply damaged sites
low-dose hyper-sensitivity
low-dose apoptosis
DDC notations: 610 Medicine and health
Publikation type: Journal Article
Abstract: Most ionizing radiation produces δ-rays of ≈1 keV that can impart MGy doses to 100 nm3 volumes of DNA. These events can produce severe dual double-strand breaks (DDSBs) on nucleosomes, particularly in dense heterochromatic DNA. This is the most common multiply damaged site, and their probabilities determine the biological effectiveness of different types of radiation. We discuss their frequency, effect on cell survival, DNA repair, and imaging by gold nanoparticle tracers and electron microscopy. This new and valuable nanometer resolution information can be used for determining the optimal tumor cure by maximizing therapeutic effects on tumors and minimizing therapeutic effects on normal tissues. The production of DDSBs makes it important to deliver a rather high dose and LET to the tumor (>2.5 Gy/Fr) and at the same time reach approximately 1.8–2.3 Gy of the lowest possible LET per fraction in TP53 intact normal tissues at risk. Therefore, their intrinsic low-dose hyper-sensitivity (LDHS)-related optimal daily fractionation window is utilized. Before full p53 activation of NHEJ and HR repair at ≈½ Gy, the low-dose apoptosis (LDA) and LDHS minimize normal tissue mutation probabilities. Ion therapy should thus ideally produce the lowest possible LET in normal tissues to avoid elevated DDSBs. Helium to boron ions can achieve this with higher-LET Bragg peaks, producing increased tumor DDSB densities. Interestingly, the highest probability of complication-free cure with boron or heavier ions requires a low LET round-up for the last 10–15 GyE, thereby steepening the dose response and further minimizing normal tissue damage. In conclusion, the new high-resolution DSB and DDSB diagnostic methods, and the new more accurate DNA-repair-based radiation biology, have been combined to increase our understanding of what is clinically important in curative radiation therapy. In fact, we must understand that we already passed the region of optimal LET and need to go back one step rather than forward, with oxygen being contemplated. As seen by the high overkill and severely high LET in the distal tumor and the increased LET to normal tissues (reminding of neutrons or neon ions), it is therefore preferable to use lithium–boron ions or combine carbon with an optimal 10–15 GyE photon, electron, or perhaps even a proton round-up, thus allowing optimized, fractionated, curative, almost complication-free treatments with photons, electrons, and light ions, introducing a real paradigm shift in curative radiation therapy with a potential 5 GyE tumor boost, 25% increase in complication-free cure and apoptotic–senescent Bragg Peak molecular light ion radiation therapy.
DOI of the first publication: 10.3390/biophysica3040045
URL of the first publication: https://doi.org/10.3390/biophysica3040045
Link to this record: urn:nbn:de:bsz:291--ds-413540
hdl:20.500.11880/37100
http://dx.doi.org/10.22028/D291-41354
ISSN: 2673-4125
Date of registration: 8-Jan-2024
Description of the related object: Supplementary Materials
Related object: https://www.mdpi.com/article/10.3390/biophysica3040045/s1
Faculty: M - Medizinische Fakultät
Department: M - Radiologie
Professorship: M - Keiner Professur zugeordnet
Collections:SciDok - Der Wissenschaftsserver der Universität des Saarlandes

Files for this record:
File Description SizeFormat 
biophysica-03-00045.pdf21,55 MBAdobe PDFView/Open


This item is licensed under a Creative Commons License Creative Commons