1

Evaluating 99mTc Auger electrons for targeted tumor

radiotherapy by computational methods

Adriana Alexandre S. Tavares a) and João Manuel R. S. Tavares b)

Faculdade de Engenharia da Universidade do Porto (FEUP)

Rua Dr. Roberto Frias, S/N, 4200-465, Porto, Portugal

Abstract:

Purpose: Technetium-99m (99mTc) has been widely used as an imaging agent but only

recently has been considered for therapeutic applications. This study aims to analyze

the potential use of 99mTc Auger electrons for targeted tumor radiotherapy, by evaluating

the DNA damage and its probability of correct repair and by studying the cellular

kinetics, following 99mTc Auger electrons irradiation in comparison to Iodine-131 (131I)

beta minus particles and Astatine-211 (211At) alpha particle irradiation.

Methods: Computational models were used to estimate the yield of DNA damage (fast

Monte Carlo damage algorithm), the probability of correct repair (Monte Carlo excision

repair algorithm) and cell kinetic effects (virtual cell radiobiology algorithm) after

irradiation with the selected particles.

Results: The results obtained with the algorithms used suggested that 99mTc CKMMX (all

M-shell Coster-Kroning – CK – and super CK transitions) electrons and Auger MXY (all

M-shell Auger transitions) have a therapeutic potential comparable to high linear energy

transfer (LET) 211At alpha particles and higher than 131I beta minus particles. All the other

99mTc electrons had a therapeutic potential similar to 131I beta minus particles.

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Conclusions: 99mTc CKMMX electrons and Auger MXY presented a higher probability to

induce apoptosis than 131I beta minus particles and a probability similar to 211At alpha

particles. Based on the results here, 99mTc CKMMX electrons and Auger MXY are useful

electrons for targeted tumor radiotherapy.

Keywords: targeted tumor radiotherapy; computational methods;

I. Introduction

The main characteristics of an ideal radionuclide for targeted tumor radiotherapy include1:

(a) electrons emitted with energies lower than 40 keV; (b) photonic emission/electron emission ratio

lower than 2; (c) half-life between 30 minutes and 10 days; (d) stable daughter nuclide or daughter

nuclide with a half-life greater than 60 days; (e) amenable to radiolabeling; (f) economical

preparation with high specific activity and radiochemical purity; and (g) efficient incorporation into a

selective carrier molecule, which should be able to associate with the DNA complex for the time

corresponding to the radionuclide half-life. Other requisites for successful targeted tumor

radiotherapy have also been highlighted such as: (a) consecutive internal irradiations using Auger

electron emitters must be possible; and (b) systemic radiation therapy must target the radiation

homogeneously on a large proportion of all live cancerous cells.2

Auger electrons have been recognized as potentially useful for targeted tumor

radiotherapy, especially due to the Auger electron range (which is in the nanometer order), and the

high ionization density of these electrons.2-6 Previous studies also demonstrated that once Auger

electron emitters are introduced close to DNA, the survival curves are similar to those obtained with

high LET α particles.5, 7 Despite these advantages, Auger emitters still have limitations including:

long tracer retention times in blood flow and low penetration in certain tumor areas, which can lead

to non-uniform doses absorbed in tumors.4

It is well known that 99mTc emits less than 1% Auger electrons per decay versus 3.7 to

19.9% for Iodine-125 (125I), Iodine-123 (123I) and Thallium-201 (201Tl). Nevertheless, some potential

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advantages have been pointed out, including: a short half-life; a stable daughter nuclide; Auger

electron energies between 0.9 and 15.4 keV; and good availability. Also 99mTc is obtained

economically, as it can be eluted and handled easily from a generator with high specific activity.

Furthermore, its ideal characteristics for imaging can allow therapy monitoring and follow-up.1-2, 8-10

These characteristics and the very small number of studies concerning 99mTc Auger electrons (for a

review see 11) motivated us to carry out this work to evaluate the usefulness of these specific Auger

electrons for targeted tumor radiotherapy. We used cell radiobiology software12 and two fast Monte

Carlo simulators12-13 to:

• Study the radiobiological effects of 99mTc Auger electrons by comparing these with other

particles emitted by radionuclides currently used for systemic radiotherapy, namely, 131I (beta

minus emitter) and 211At (alpha emitter).

• Evaluate the radiobiological effects of 99mTc Auger electrons in comparison with 131I beta minus

and 211At alpha particles on two different cell types (human fibroblasts and human intestinal

crypt cells).

II. Methods

Three different computational simulators were used to study the therapeutic potential of

99mTc Auger electrons12-13. This section explains the main principles of these simulators and points

out the parameters adopted.

2.1 - Fast Monte Carlo Damage Formation Simulator

The Monte Carlo damage simulation (MCDS) algorithm is used to predict the types of

DNA damage and their yield after irradiation. The model generates a random number of damage

configurations expected within the DNA of one cell. This algorithm processes information in two

main steps: 1) it randomly distributes, in a DNA segment, the expected amount of damage

produced in a cell and 2) subdivides the distribution of damage in that section. The number and

spatial distribution of damage configurations predicted by the MCDS algorithm are in reasonable

agreement with those predicted by track-structure simulations. Furthermore, the MCDS allows the

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collection of data from multiple irradiation scenarios within a few minutes on a common computer.

These characteristics make the MCDS simulator useful for comparing 99mTc electrons with other

particles used for radiotherapy.14 For a detailed description of the MCDS model as well as

additional discussions on the validity and limitations of the model, see, for example, 14-15.

The classification scheme used by the MCDS to categorize DNA damage is based on the

classification parameters proposed by Nikjoo et al. (1997), and it comprises essentially: (a) no

damage; (b) single-strand breaks (SSB); (c) two strand-breaks on the same strand (SSB+); (d) two

or more strand-breaks on opposite strands separated by at least 10 base pairs (2SSB); (e) two

strand-breaks on opposite strands with a separation not greater than 10 base pairs (double strand

breaks - DSB); (f) DSB accompanied by one (or more) additional strand breaks within a 10-base

pair separation (DSB+); and (g) more than one DSB, whether within the 10-base pair separation or

further apart (DSB++). For further details see 16-17.

2.2 - Fast Monte Carlo Excision Repair Simulator

The Monte Carlo excision repair (MCER) algorithm is used to simulate repair outcomes

such as correct repair, repair with a mutation and conversion into a DSB. This Monte Carlo

simulation also calculates the formation and repair of damage within one cell.13

The MCER algorithm starts using the MCDS algorithm to generate a random number of

damage configurations expected within the DNA of one cell. Thereafter, the MCDS-generated

damage configurations are superimposed over an actual nucleotide sequence or a random

nucleotide sequence. Finally, the MCER model is used to simulate the repair, misrepair and

aborted excision repair of damage within the entire genome or within a specific region of the DNA.

The lesions forming a cluster are removed sequentially through repeated rounds of excision repair.

Most DNA oxidative damage, including modified apurinic/apyrimidinic (AP) converted to

strand breaks, require repair by base excision repair (BER). Two different types of BER processes

have been observed in eukaryotic and prokaryotic cells: 1) excision and replacement of a single

nucleotide, known as short-patch BER (SP-BER), which occurs in the majority of cases; and 2)

replacement of 2 to 13 nucleotides, known as long-patch BER (LP-BER). Another enzymatically

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distinct repair pathway is nucleotide excision repair (NER). This last repair pathway, observed in

eukaryotic cells, substitutes oligonucleotide fragments of 24 to 32 nucleotides in length.13 The

simulator results are presented in terms of three simplified repair scenarios due to the current

uncertainties associated with the processing of radiation-induced damage by the BER and NER

pathways. According to Semenenko et al. (2005), the simulator results correlate well with in vitro

results from cell cultures, despite this simplification.18

A detailed description of the MCER algorithm as well as additional discussions on the

validity and limitations of the model can be found in 13, 18.

2.3 - Virtual Cell Radiobiology Simulator

Ionizing radiation frequently causes DSB and other DNA damages in less than one

millisecond. Radiation induced damage is processed slowly via enzymatic repair and misrepair,

which then determines the fate of the irradiated cell. As far as long time scales are concerned, cell

cycle kinetics can influence and be influenced by the kinetics of damage processing.19 DNA

damage is a trigger for apoptosis, although cell membrane damage can also induce apoptosis.15

The dose-response association, damage production and its repair mechanisms have been

largely studied using radiobiological models that correlate the dose rate with cell response. Some

of the existing models include: 1) the repair-misrepair model (RMR), 2) lethal-potentially lethal

model (LPL) and 3) two-lesion kinetics (TLK).19 The main disadvantage of the LPL model is its

limits to correlate the biochemical processes of DSB with cell death. The RMR and linear quadratic

models also have the same limitation. In order to overcome this limitation, the TLK model carries

out an improved correlation between the biochemical processes of DSB and cell death by

subdividing DSB into simple or complex DSBs. This subdivision is important, since simple and

complex DSBs have different repair characteristics.20 Therefore, simulations carried out with the

virtual cell radiobiology simulator (VC) were performed using the TLK model.12

2.4 - Simulated Parameters

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The 99mTc spectrum of energies, presented in an AAPM (American Association of

Physicists in Medicine) report in 1992, includes electron ranges from 2.05 nm to 251 μm and

electron energies ranging between 0.033 keV and 140 keV.21 In the present study, all 99mTc

electrons were studied with the exception of Auger CK NNX (all N-shell CK and super CK

transitions), due to its low energy (33 eV), which is below the lower energetic limit of the simulator

(80 eV). In addition, alpha particles from 211At and beta minus particles from 131I were also studied.

Further input details for the MCDS and MCER simulators can be found in Table I.

Once the comparison between the MCDS and MCER results for 99mTc electrons, 131I beta

particles and 211At alpha particles was complete, the two best 99mTc electrons (with the highest

ability to induce DNA damage) were then used to study the kinetics of the cell after irradiation in

two different cell types: 1) human fibroblasts (Tc – the cell cycle time =0.900 hour and Tpot -

potential doubling time=0.667 days) and 2) human intestinal crypt cells (Tc=1.000 hour and

Tpot=1.625 days) 22-23. The cell kinetic study (VC simulator) compared the two best 99mTc electrons

with 131I beta particles and 211At alpha particles.

The number of DSBs and the percentage of complex DSBs were obtained from the MCDS

simulator. These results were then applied as input parameters for the TLK model used on the VC

simulator. Irradiation periods of 2, 6 and 24 hours (TCUT – time allowed for repair after exposure),

with total absorbed doses of 1, 1.5 and 2 Gy were studied using the VC simulator. Other

parameters used on the VC simulator, specified in the TLK model input file, include: 1) DRM

(damage repair model)=TLK; 2) CKM (cell kinetics model)=QECK (quasi-exponential cell kinetics

model); 3) DNA (cell DNA content)=5.667D+09 base pair; 4) DSB (endogenous)=4.3349E-03 Gy-1

cell-1; 5) RHT (repair half-time)=XXX, XXX=0.25, 9 hours (simple DSBs are repaired faster than

complex DSBs); 6) A0 (probability of correct repair)=AAA, AAA=0.95, 0.25 (simple DSBs are

repaired more accurately than complex DSBs); 7) ETA (pairwise damage interaction rate)=2.5E-04

h-1; 8) PHI (probability of a misrejoined DSB being lethal)=0.005; 9) GAM (fraction of binary-

misrepaired damages that are lethal)=0.25; 10) N0 (initial number of cells)=1000; 11) KAP (peak

cell density)=1.0D+38 cells per cm3; 12) VOL (tissue volume)=1 cm3; 13) FRDL (fraction of residual

that is lethal damage)=0.5; 14) ACUT (absolute residual-damage cutoff)=1.0D-09 expected number

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of DNA damages per cell; 15) BGDR (average background absorbed dose rate on planet

Earth)=2.73748E-07 Gy/h; 16) DCUT (dose cutoff)=0.01 Gy; 17) STOL (step-size tolerance)=0.01

Gy/h; 18) SAD (scaled absorbed dose)=RX1, RX1=1, 1.5, 2 Gy; 19) GF (growth fraction, if 0 (zero)

all cells are quiescent, if 1 (one) all cells are cycling and if 0.5 the cell population is

heterogeneous)=0, 0.5, 1.12, 24

2.5 - Statistical Analysis

The MCDS results are expressed as a percentage of damage. The MCER results are

expressed as a probability of repair or number of cell cycles. The VC values are expressed as the

number of lethal damages per cell, number of surviving cells, probability per cell and frequency per

irradiated cell. The statistical significance was determined using either the Student t-test or ANOVA

(p<0.01) for each group of irradiating agents.

III. Results

3.1 - MCDS and MCER Results

Results obtained by the MCDS simulator allowed an estimate to be made of the amount of

DNA damage following irradiation with 99mTc electrons, 131I beta minus particles and 211At alpha

particles, as shown in Fig. 1. Results for the probability of correct repair, repair with a mutation and

conversion into a DSB are presented in Fig. 2 and the number of repair cycles is presented in Fig.

3 (MCER simulator).

Findings from the MCDS and MCER simulators showed that CKMMX electrons and Auger

MXY were the best 99mTc electrons for targeted tumor radiotherapy. Accordingly, these electrons

were used for the study of cell kinetics after irradiation with the VC simulator.

3.2 - VC Simulator

The results of mutagenesis probability and induction of enhanced genetic instability

(defined by the algorithm used as PGA×PGH×NCG=4.250E-06, with: PGA - probability a mutated

gene induces genomic instability, PGH - probability that a randomly formed mutation hits a critical

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gene and NCG - total number of target genes that must be damaged to induce genomic instability)

after irradiation with different irradiating agents are shown in Fig. 4a. Statistical analysis showed

significant differences between 99mTc Auger MXY and 131I beta minus particles (p=0.001, t-test) and

also between 211At alpha particles and 131I beta minus particles (p=0.0006, t-test). The estimated

number of lethal damages per cell due to mutations for all the irradiating agents is presented in Fig.

4b. Additionally, statistically significant differences were observed among the different irradiating

agents (p<0.0001, ANOVA). Results for the neoplastic transformation (defined by the algorithm

used as a function of dose and dose rate at t=42.0 days) per studied cell for different irradiating

agents are presented in Fig. 4c. Once again, statistically significant differences were found among

each irradiating agent per studied cell type (fibroblasts and intestinal crypt cells), p<0.0001

(ANOVA).

The estimated number of cells that survived irradiation when all cells were quiescent;

when the cell population was heterogeneous (with quiescent cells and cells actively dividing/on

cycle); and when all cells were actively dividing is presented in Figs. 5a, 5b and 5c, respectively.

Statistically significant differences were observed between 131I beta minus particles and the other

types of radiation when all cells were quiescent (p<0.0001, ANOVA). However, no differences were

found between 99mTc Auger electrons and 211At alpha particles or between fibroblasts and intestinal

crypt cells for all the irradiating agents (Fig. 5a). In contrast, heterogeneous populations yielded

statistically significant differences between different cell types for the same irradiating agent

(p<0.0001, t-test). Differences among distinct types of irradiating agents in intestinal crypt cells

(p<0.0001, ANOVA) and fibroblasts (p=0.0031, ANOVA) were also found in heterogeneous

populations (Fig. 5b).

For populations of cells actively dividing (Fig. 5c), statistically significant differences were

found among distinct irradiating agents in intestinal crypt cells (p=0.0002, ANOVA), but no

differences were found among distinct irradiating agents in fibroblasts (p=0.3014, ANOVA). A more

detailed analysis showed that no differences were observed between both 99mTc Auger electrons

(CKMMX and Auger MXY, p=0.1406, t-test) or among each 99mTc Auger electron under study and

211At alpha particles (CKMMX, p=0.1103 and Auger MXY, p=0.8897 – t-test). Nevertheless,

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statistically significant differences were observed when comparing 131I beta minus particles with the

other particles studied (p<0.0001, t-test). Finally, statistically significant differences were also

observed when comparing the same irradiating agent on the two distinct cell types (p<0.0001, t-

test).

IV. Discussion and Conclusions

MCDS results showed that the percentage of simple and double strand breaks after

irradiation was always higher for 99mTc CKMMX electrons and Auger MXY than for 131I beta minus

particles and was similar to 211At alpha particles. The same trend was observed for the percentage

of complex single and double strand breaks. Furthermore, the remaining 99mTc electrons obtained

by internal conversion were less able to induce DNA damage, which correlates with Pomplun et al.

(2006).25 The results obtained with these conversion electrons were similar to 131I beta minus

particles. This may be explained by the higher tissue range of these 99mTc electrons, whose

behavior is similar to beta minus particles (low LET particles).

The MCER outcome showed that the increased amount of DNA damage and its

complexity hampers successful repair. Moreover, the probability of correct repair of single strand

breaks is lower for 99mTc CKMMX electrons and Auger MXY than for 131I beta minus particles and is

comparable to 211At alpha particles. The probability of conversion to DSBs is also higher for 99mTc

electrons than for 131I beta minus particles. These results were observed for all the repair processes

studied, regardless of the repair route. In addition, a higher number of repair cell cycles had been

correlated with prolonged repair times, which correlates with increased LET particles. Previous

studies observed that complex damage repair by excision leads to an increased number of DSBs.13

Accordingly, it is well known that DNA double strand breaks are frequently associated with

apoptosis induction.15 Therefore, the observed higher number of DNA double strands induced by

99mTc CKMMX electron and Auger MXY (MCDS simulator) allied to its higher DNA single strand

breaks conversion to double strand breaks (MCER simulator), suggest that the probability of

apoptosis induction is likely to be higher for those electrons than for 131I beta minus particles and

comparable to 211At alpha particles.

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The mutagenesis and enhancement of genetic instability study showed that the best 99mTc

Auger electrons (99mTc CKMMX electron and Auger MXY) had a higher probability of inducing

mutagenesis and genetic instability than 131I beta minus. However, 131I beta minus particles were

the most likely of all the irradiating agents studied to induce neoplastic transformation. Furthermore,

the selected 99mTc Auger electrons had a higher ability to induce lethal damage, due to mutations,

than the other particles studied. These results suggest that the higher probability of induced

mutagenesis and enhancement of genetic instability of the selected Auger electrons will potentially

lead to cell death or benign mutations and not to neoplastic transformation. The findings obtained

are consistent with in vitro studies conducted by Pedraza-López et al. (2000) and Ilknur et al.

(2002) using lymphocytes.26-27

The results showed that the various irradiating agents were equally effective at killing

quiescent human fibroblast and intestinal crypt cells. In contrast significant differences were seen

between irradiating agent and cell types when a mixed population of cycling and quiescent cells

were irradiated. These observations highlight the influence of cell proliferation on the

radiosensitivity of the cells. For heterogeneous populations, crypt cells were more radiosensitive

than fibroblasts. Finally, for cell populations where all cells were actively dividing, the results also

showed that the number of cells that survive irradiation was significantly lower for intestinal crypt

cells when compared to fibroblasts. Nevertheless, no differences were observed among the distinct

irradiating agents studied for actively dividing fibroblast populations, which suggests that cell

response to irradiation is radiation type independent. This may be explained by the reduced

radiosensitivity of this type of cell and its active proliferation state, which may compensate radiation

induced damages by fast continuous cell duplication. Furthermore, intestinal crypt cells showed

significant differences among all irradiating agents. This may mean that, due to its longer doubling

time (39 hours versus 16 hours for fibroblasts), intestinal crypt cells were unable to compensate

radiation induced damage by cell duplication.

Häfliger and coworker’s in vitro studies (2005) showed that 99mTc induced double-strand

breaks in DNA when decaying in its direct vicinity.21, 28 In their paper, Häfliger and coworkers cited

the Ftacnikova and Bohm (2000) study regarding theoretical calculations of energy deposition into

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DNA.28-29 According to Ftacnikova and Bohm (2000), the electrons with initial energies from 50 eV

to 250 eV have the highest theoretical probability of inducing DNA DSB, because these electrons

are able to produce clusters of inelastic interactions in a volume with a diameter of a few nm (which

is characteristic of Auger emitters).29 Based on that, Häfliger et al. listed the Auger electrons

emitted by 99mTc that are potentially the most interesting for targeted tumor radiotherapy: CK MMX

electron, Auger MXY electron and CK NNX electron.28 We used different computational methods to

evaluate the 99mTc electrons spectrum by comparing those with other particles used for

radiotherapy. This represents a novel and faster method to evaluate and grade 99mTc electrons for

target tumor radiotherapy. All 99mTc electrons were considered separately (except CK NNX electron

due to simulator limitations) and their radiobiological effects evaluated. Our findings, obtained by

means of three different computational simulators, provided evidence that 99mTc CK MMX electron

and Auger MXY electron are useful electrons for targeted tumor radiotherapy.

99mTc Auger MXY and CKMMX electrons yield 1.1 and 0.747 electrons per decay - the

second and third highest yields of all 99mTc Auger electrons, respectively. The uppermost yielding

electrons are CKNNX with 1.98 electrons per decay, which was not evaluated due to previously

explained simulator limitations. These yields are lower than those for 125I, which yields 1.44 and

3.38 electrons per decay for CKMMX electrons and Auger MXY, respectively.21 Nevertheless, this

potential limitation may be overcome or compensated by the 99mTc shorter half-life, as shown by

previous studies.1, 8, 10 Moreover, the 99mTc electron irradiation results correlate with previous

findings suggesting that the shorter half-life radionuclides reduce the dose fractioning to daughter

cells and increase the absorbed doses per unit of time.1-6

Higher DNA damage yields have been associated with Auger electrons due to their short

range and LET quality. The high abundance of 99mTc photons is an important factor that may

influence the possible therapeutic outcome. Although photons emitted present a high tissue range

and thus most energy will be deposited outside the target cell, their dosimetric implications may

work as a limiting factor for this kind of target tumor radiotherapy. Nonetheless, these photons

could facilitate therapy monitoring and the design of more selective and specific carriers. This may

be challenging but would allow the delivery of radiation to a specific targeted cell.

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Computational methods allow rapid and easy data collection. Nonetheless, some

limitations have been pointed out, including modeling and evaluation based on current knowledge,

which works as a mechanistic process. This disadvantage may underestimate or overestimate the

results. Although the results obtained showed correlation with previous in vitro and other

computational studies, which suggest that the simulators used may be useful for the

characterization of different particles for targeted tumor radiotherapy, further comparison of 99mTc

electrons with other Auger and conversion electrons could provide extra information regarding the

potential of 99mTc as a therapeutic radionuclide.

In summary, this study aimed to compare different irradiating agents using the same

exposure conditions and controllable cell populations to clarify the potential usefulness of 99mTc

electrons for targeted tumor radiotherapy. An analysis of all the data obtained has led us to

conclude that 99mTc CKMMX electron and Auger MXY presents a higher probability to induce

apoptosis than 131I beta minus particles and a similar one to 211At alpha particles. This characterizes

99mTc CKMMX electron and Auger MXY as high LET particles and thus useful for targeted tumor

radiotherapy.

Acknowledgement

The authors wish to thank Dr Robert Stewart (School of Health Sciences – Purdue University, USA)

for providing the simulator software packages used and for his kind technical assistance.

References:

a) Electronic email: adriana_tavares@msn.com

b) Electronic email: tavares@fe.up.pt

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TABLE CAPTION

Table I. Input conditions for MCDS and MCER simulators.

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TABLE I

Particle Energy [MeV]

Yield/Decay Input conditions

CK MMX 0.000116 0.7470

MCDS e MCER: Initial cell number = 1000

DMSO concentration = 0 (normal cell environment)

MCER:

Inhibition distance = 3 bp Probability of choosing a lesion from the first

strand break (P1) = 0.5 Polymerase error rate for SP-BER=1.0-4

Polymerase error rate for LP-BER and NER = 1.0-6

Probability of incorrect insertion opposite damaged base = 0.75

Probability of incorrect insertion of opposite base lost = 0.75

Auger MXY 0.000226 1.1000

Auger LMM 0.002050 0.0868

Auger LMX 0.002320 0.0137

Auger LXY 0.002660 0.0012

Auger KLL 0.015300 0.0126

Auger KLX 0.017800 0.0047

IC 1 M, N… 0.001820 0.9910

IC 2 K 0.119000 0.0843

IC 3 K 0.122000 0.0136

IC 2 L 0.137000 0.0037

IC 3 L 0.140000 0.0059

IC 2 M, N… 0.140000 0.0025

Beta - 131I 0.606000 0.8930

Alpha - 211At 6.790000 1.0000

18

FIGURE CAPTIONS

Fig. 1. a) Percentage of DNA radioinduced SSB and DSB after irradiation with 99mTc electrons, 131I

beta minus particles and 211At alpha particles (MCDS simulator). b) Percentage of two SSB on the

same DNA segment (2SSB/DNA seg), two or more SSB on opposite DNA segments and separated

by at least 10 base pairs (2 or +SSB DNA); and percentage of one DSB and one or more SSB

separated by a maximum of 10 base pairs (DSB & 1 or + SSB) and one or more DSB separated by

a maximum of 10 base pairs (1 or +DSB 10 bp), after irradiation with 99mTc electrons, 131I beta

minus particles and 211At alpha particles (MCDS simulator). c) Fraction of complex SSB and DSB

DNA damages after irradiation with 99mTc electrons, 131I beta minus particles and 211At alpha

particles (MCDS simulator).

Fig. 2. Probability of correct repair (p correct), repair with mutation (p mutation) and conversion to

DSB (p conversion DSB) of DNA SSB, by SP-BER, LP-BER, SP-NER and LP-NER repair methods

(MCER simulator).

Fig. 3. Average number of repair cycles for all used repair methods and irradiating agents (MCER

simulator).

Fig. 4. a) Results from mutagenesis probability and induction of enhanced genetic instability

simulations; b) average number of lethal mutations per cell; c) neoplastic transformation frequency

in two different selected cell types after irradiation with distinct irradiating agents. Simulated doses

of 1, 1.5 and 2 Gy during irradiation periods of 2, 6 and 24 hours (VC simulator).

Fig. 5. Number of cells that survive irradiation with different irradiating agents a) in a quiescent cell

population; b) in a heterogeneous cell population and; c) in cells actively dividing. Simulated doses

of 1, 1.5 and 2 Gy during irradiation periods of 2, 6 and 24 hours (VC simulator).

19

FIGURES

Figure 1

20

Figure 2

Figure 3

21

Figure 4

Figure 5