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: [email protected]
b) Electronic email: [email protected]
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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