How to explain the sensitivity of DNA double-strand breaks yield to 125I position?

TL;DR

This study uses Monte Carlo simulations to analyze how the position of 125I affects DNA double-strand break yields, emphasizing the importance of damage probability in the proximal strand due to Auger electron emissions.

Contribution

It provides detailed modeling of energy deposit variations with 125I position, highlighting the significance of strand proximity in DSB induction for targeted therapy.

Findings

Dose per decay drops sharply in the proximal strand when 125I moves away from DNA

Energy deposition in the proximal strand is more sensitive to 125I position than in the entire DNA cylinder

Positioning of Auger emitters is crucial for optimizing targeted radionuclide therapy

Abstract

Purpose: Auger emitters exhibit interesting features due to their emission of a cascade of short-range Auger electrons. Maximum DNA breakage efficacy is achieved when decays occur near DNA. Studies of double-strand breaks (DSBs) yields in plasmids revealed cutoff distances from DNA axis of 10.5-12 {\AA}, beyond which the mechanism of DSBs moves from direct to indirect effects, and the yield decreases rapidly. Some authors suggested that the average energy deposited in a DNA cylinder could explain such cutoffs. We aimed to study this hypothesis in further detail.Materials and methods: Using the Monte Carlo code CELLDOSE, we investigated the influence of the 125I atom position on energy deposits and absorbed doses per decay not only in a DNA cylinder, but also in individual strands, each modeled as 10 spheres encompassing the fragility sites for phosphodiester bond cleavage.Results: The dose per decay decreased much more rapidly for a sphere in the proximal strand than for the DNA cylinder. For example, when moving the 125I source from 10.5 {\AA} to 11.5 {\AA}, the average dose to the sphere dropped by 43%, compared to only 13% in the case of the cylinder.Conclusions: Explaining variations in DSBs yields with 125I position should consider the probability of inducing damage in the proximal strand (nearest to the 125I atom). The energy received by fragility sites in this strand is highly influenced by the isotropic (4$\pi$) emission of 125I low-energy Auger electrons. The positioning of Auger emitters for targeted radionuclide therapy can be envisioned accordingly.