Monte Carlo simulations and measurement of DNA damage from x-ray-triggered Auger cascades in iododeoxyuridine (IUdR)

Abstract

We investigated the DNA damage from Auger electrons emitted from incorporated stable iodine (127I), following photoelectric absorption of external x-rays. The effectiveness of the Auger electrons in producing DNA double-strand breaks (DSB) was determined theoretically, using Monte Carlo simulations of the radiation physics and chemistry, and was shown to be in reasonable agreement with DNA damage measured using the comet assay. The DSB yields were measured in CHO cells for 60Co (as a non-Auger-promoting radiation) and for tungsten-filtered 100 kVp x-rays capable of producing Auger electron emission. The theoretical study showed that on average, 2.5 Auger electrons were emitted for N-shell orbital vacancies and up to 10 Auger electrons were emitted from L1-shell vacancies. These Auger bursts produced approximately 0.03 DSB per N-shell vacancy and 0.3 DSB per K-shell or L-shell vacancy. The calculated yield of DSB from Auger cascades per unit dose (1 Gy) in water was approximately 1.7 for tungsten-filtered 100 kVp x-rays, assuming 20% IUdR substitution of thymidine. The comet assay yielded an experimental value of 3.6+/-1.6 per 1 Gy for the same conditions. The Monte Carlo simulations also demonstrated a high complexity of DSB produced by Auger cascades with virtually all DSB from inner shell orbitals (i.e. K, L shells) accompanied by compounded strand breakage and base damage, indicating a difficult lesion to repair. This finding agrees well with comet assay results of DNA repair, where an increase in the DSB yield in IUdR-sensitized cells was shown to persist after a time of 24 h. We conclude that Auger cascades in iodine produce a modest increase in the number of initial strand breaks of the order of 10% but the complex nature of these DSB makes them very difficult to repair or potentially prone to misrepair. The accentuated DNA damage may have major consequences for cell survival and may be exploitable in kilovoltage photon activation therapy (PAT) of tumors sensitized with iodine.

Synchrotron radiation-based experimental determination of the optimal energy for cell radiotoxicity enhancement following photoelectric effect on stable iodinated compounds

“…The choice of the optimal X-ray energy for irradiating IUdR pretreated cells is investigated in the present work, similarly to Karnas et al (1999Karnas et al ( , 2001a. Theoretical calculation of the DER relative to the presence of 10 mM of IUdR during the irradiation in water would be negligible, very close to 1, except if this factor is calculated at the microscopic level, as suggested by Karnas et al In that case, a DER comprised between 2 and 3 for 50 keV irradiation is expected for a 10 -30% thymidine base replacement by iodine.…”

Dependence of Cell Survival on Iododeoxyuridine Concentration in 35-keV Photon-Activated Auger Electron Radiotherapy

“…At such energy it is possible that a photoelectric absorption will occur, followed by emission of Auger electrons. For a K-shell vacancy in iodine, 90% of the Auger electrons have energies less than 1 keV, with an average energy of 0.78 keV, corresponding to a dose-deposition range in water of approximately 60 nm (12). These Auger electrons produce a dense distribution of ionizations, similar to alpha particles (13), with the ability to cause single-strand breaks and double-strand breaks (DSB) in the DNA.…”

“…They calculated 10.4 photoelectric events per cell per Gy for a 33.2-keV photon beam, which should generate approximately 7 DSB per cell per Gy. These additional DSBs hypothetically are very difficult or impossible for the cell to repair correctly because they consist of locally multiply damaged sites (3,12,15).…”

“…Conventional low linear energy transfer (LET) radiation produces approximately 30 DSB per Gy in Chinese hamster ovary (CHO) cells (12,14). Karnas et al (12) measured an increased yield due to Auger electrons of 3.4 DSB per cell per Gy of dose to water using tungsten-filtered 100-kVp xrays in CHO cells with 18% thymidine replacement by IUdR.…”

The effect of energy spectrum change on DNA damage in and out of field in 10-MV clinical photon beams

“…Most MC microdosimetry codes use a simple DNA model that can be used to analyze the effect of different types of radiation to determine a link between the RBE of low-and high-linear energy transfer radiation [3,8,14,15,17,25,26,29]. The use of the condensed history track method in macrodosimetric MC for electron transport reduces simulation time when compared to microdosimetric MC codes that track particle transportation event by event.…”