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14 July 2022 Quantifying Cellular Repair, Misrepair and Apoptosis Induced by Boron Ions, Gamma Rays and PRIMA-1 Using the RHR Formulation
Anders Brahme
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The recent interaction cross-section-based formulation for radiation-induced direct cellular inactivation, mild and severe sublethal damage, DNA-repair and cell survival have been developed to accurately describe cellular repair, misrepair and apoptosis in TP53 wild-type and mutant cells. The principal idea of this new non-homologous repairable-homologous repairable (RHR) damage formulation is to separately describe the mild damage that can be rapidly handled by the most basic repair processes including the non-homologous end joining (NHEJ), and more complex damage requiring longer repair times and high-fidelity homologous recombination (HR) repair. Taking the interaction between these two key mammalian DNA repair processes more accurately into account has significantly improved the method as indicated in the original publication. Based on the principal mechanisms of 7 repair and 8 misrepair processes presently derived, it has been possible to quite accurately describe the probability that some of these repair processes when unsuccessful can induce cellular apoptosis with increasing doses of γrays, boron ions and PRIMA-1. Interestingly, for all LETs studied (≈0.3–160 eV/nm) the increase in apoptosis saturates when the cell survival reaches about 10% and the fraction of un-hit cells is well below the 1% level. It is shown that most of the early cell kill for low-to-medium LETs are due to apoptosis since the cell survival as well as the non-apoptotic cells agree very well at low doses and other death processes dominate beyond D > 1 Gy. The low-dose apoptosis is due to the fact that the full activation of the checkpoint kinases ATM and Chk2 requires >8 and >18 DSBs per cell to phosphorylate p53 at serine 15 and 20. Therefore, DNA repair is not fully activated until well after 1/2 Gy, and the cellular response may be apoptotic by default before the low-dose hyper sensitivity (LDHS) is replaced by an increased radiation tolerance as the DNA repair processes get maximal efficiency. In effect, simultaneously explaining the LDHS and inverse dose rate phenomena. The partial contributions by the eight newly derived misrepair processes was determined so they together accurately described the experimental apoptosis induction data for γ rays and boron ions. Through these partial misrepair contributions it was possible to predict the apoptotic response based solely on carefully analyzed cell survival data, demonstrating the usefulness of an accurate DNA repair-based cell survival approach. The peak relative biological effectiveness (RBE) of the boron ions was 3.5 at 160 eV/nm whereas the analogous peak relative apoptotic effectiveness (RAE) was 3.4 but at 40 eV/nm indicating the clinical value of the lower LET light ions (15 ≤ LET ≤ 55 eV/nm, 2 ≤ Z ≤5) in therapeutic applications to maximize tumor apoptosis and senescence. The new survival expressions were also applied on mouse embryonic fibroblasts with key knocked-out repair genes, showing a good agreement between the principal non-homologous and homologous repair terms and also a reasonable prediction of the associated apoptotic induction. Finally, the formulation was used to estimate the increase in DNA repair and apoptotic response in combination with the mutant p53 reactivating compound PRIMA-1 and γ rays, indicating a 10–2 times increase in apoptosis with 5 µM of the compound reaching apoptosis levels not far from peak apoptosis boron ions in a TP53 mutant cell line. To utilize PRIMA-1 induced apoptosis and cellular sensitization for reactive oxygen species (ROS), concomitant biologically optimized radiation therapy is proposed to maximize the complication free tumor cure for the multitude of TP53 mutant tumors seen in the clinic. The experimental data also indicated the clinically very important high-absorbed dose ROS effect of PRIMA-1.

©2022 by Radiation Research Society. All rights of reproduction in any form reserved.
Anders Brahme "Quantifying Cellular Repair, Misrepair and Apoptosis Induced by Boron Ions, Gamma Rays and PRIMA-1 Using the RHR Formulation," Radiation Research 198(3), 271-296, (14 July 2022).
Received: 26 December 2021; Accepted: 14 June 2022; Published: 14 July 2022
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