Megavoltage radiation beams are nowadays widely used for anticancer radiotherapy.
High-energy linear accelerators allow highly penetrating radiation to treat targeted
volumes with a better sparing of superficial healthy tissues. Moreover, in this range
of energies (1–25 MeV), photons beams mainly interact with living matter by Compton
scattering processes, almost independent of the composition of the traversed material.
Thus, a highly homogeneous dose distribution is achievable in the human body and predicted
accurately by Monte-Carlo based three-dimensional treatment planning systems.
Lower energy beams are preferred for medical imaging. Kilovoltage X-ray beams are
used for the production of radiological images and the predominant physical process
in high-density materials is the photoelectric effect, which is strongly Z-dependent.
Hence, attenuation in bone is far higher than for soft tissues, and the radiological
contrast rely on photoelectric processes. The spectra of these X-ray tube beams vary
between 10 and 250 keV.
Healthy tissue tolerance remains the major limiting factor of anticancer radiotherapy
and techniques are investigated to enhance the local control of tumours by increasing
the absorbed X-ray dose, while preserving more efficiently the healthy surrounding
tissues.
Dual modalities like Boron Neutron Capture Therapy (BNCT) propose enhancing the neutron
capture reaction cross-sections in a stable boron-loaded tumour (Barth et al, 1990).
Toxicity of the irradiation is increased in the tumour by the production of high linear
energy transfer alpha and lithium ion particles. The neutron dose enhancement is highly
correlated to the boron concentration present inside the tumour at the time of the
irradiation. The most limiting factor remains the boron concentrations achievable
(Soloway et al, 1994; Coderre et al, 1998) and their in vivo measurement (Verbakel
and Stecher-Rasmussen, 2001). Nevertheless, clinical trials are underway for patients
with high-grade brain gliomas, which remains a hardly curable tumour type.
For photon beams, a bimodal approach known as ‘Photon Activation Therapy’ has been
proposed in the early 1970s (Tisljar-Lentulis et al, 1973; Tisljar-Lentulis and Feinendegen,
1977). High-Z heteroatoms in DNA could be used for increasing kilovoltage X-ray killing
efficiency, by generating photoelectric events. Ionised heavy atoms then reorganise
and emit low-energy Auger electrons cascades, able to damage DNA because of their
nuclear localisation. In a less specific way, Norman et al developed another approach:
the use of a conventional kilovoltage scanner to treat iodine-loaded tumours (Iwamoto
et al, 1990; Rose et al, 1999). By increasing the tumour density and focussing a kilovoltage
beam on it, interaction cross-sections are improved in the tumour only, due to the
photoelectric effect, and the dose distribution is concentrated inside the tumour
(Solberg et al, 1992a, 1995; Mesa et al, 1999). Moreover, tumour imaging is achievable
during treatment with this scanner. The lack of such a modality is actually a weakness
of current megavoltage radiotherapy treatments. The physical properties of high-energy
beams allow good dose distribution characteristics but do not allow good imaging yet.
What would be the optimal X-ray energy, if any, for irradiating tumours loaded with
high-Z elements? Considering a heavy element introduced to living matter as isolated
atoms, irradiation with an energy just above the K-edge appears conceptually as the
best option to enhance energy deposition by the contribution of Auger electrons events.
This concept has been tested with iodine and other heavy atoms, irradiated with either
monochromatic radioactive sources (Nath et al, 1990), or synchrotron X-rays (Laster
et al, 1993; Hieda et al, 1996). Laster et al obtained convincing results with iodine
incorporated into DNA as 5-iodo-2′-deoxyuridine (IUdR). Others, as Solberg et al (1992a)
and Karnas et al (1999) suggested, by calculation, that the optimal energy should
be far above the iodine K-edge and around 50 keV because it corresponds to the energy
level where the difference between the mass energy absorption coefficients of water
and iodine is the largest. Therefore, two different concepts were to be considered:
the first one based on the occurrence of particular events; the second one taking
into account the difference in absorption capacity of the living matter with and without
the presence of a certain concentration of iodine, whatever the structure imbedding
it.
As pointed out by Karnas et al (1999) and Solberg et al (1992b), monochromatic X-rays
produced by a synchrotron should be the best tool for verifying these hypotheses.
Powerful third generation synchrotrons are now available to deliver broad X-ray beams
(10–100 keV), brilliant enough for using monochromators and able to precisely select
the desired X-rays energy. At the European Synchrotron Radiation Facility (ESRF, Grenoble,
France), the ID17 beamline is dedicated to medical applications of synchrotron radiation
(Thomlinson et al, 2000) and is designed for human in vivo experiments (Elleaume et
al, 1999, 2000a).
In this paper we report the experimental demonstration of the existence of an optimal
value of the enhancement ratio produced by the presence of iodine compounds. We studied
its variation along the energy spectrum from 30 to 70 keV in two different experimental
settings: extracellular iodine from contrast agent and iodine incorporated into DNA
as IUdR.
METHODS AND MATERIALS
Chemicals
5-iodo-2′-deoxyuridine was provided by Lausanne University Hospital Pharmacy (Switzerland)
as lyophilised powder. Iodinated radiographic contrast agent used for extracellular
iodine was Iomeron® (Bracco, Milano, Italy), which is a nonionic, monomeric iodine
compound containing 350 mg of iodine per ml of solution.
Cell line
The SQ20B cell line was derived from a human head and neck squamous carcinoma (Weichselbaum
et al, 1986) and was obtained from William K Dahlberg (Dr JB Little Laboratory, Harvard
School of Public Health). This cell line is commonly used for radiobiological research,
and has been handled as previously described (Corde et al, 2002). The SQ20B doubling
time is 21 h.
Cell culture technique, colony-forming assay
Cells were seeded and grown as monolayer in plastic tissue culture disposable flasks
(Falcon) with 0.4 ml cm−2 Dulbecco's modified Eagle's minimum medium (Gibco-BRL),
added with 10% foetal calf serum (Gibco-BRL), penicillin and streptomycin (Gibco-BRL).
Cells were grown at 37°C in a humidified atmosphere of 5% CO2 in air.
When IUdR was used, 48 h before irradiation, cell cultures were incubated with 10 μ
M IUdR (1.3 mg iodine l−1), diluted in fresh medium. Before irradiation, cells were
trypsinised and experiments were carried out with the cell suspension in 2 ml sterile
cryotubes (Merck Eurolab) with or without Iomeron® (10 g iodine l−1) added to the
culture medium, according to the experimental protocol.
Three independent experiments have been carried out and averaged. After each irradiation,
triplicate low-density subcultures of the cells were established in ∅100 mm Petri
dishes for colony-forming assay. Colonies were fixed and stained with violet crystal
oxalate (Merck Eurolab) after 15 days of cell growing.
Irradiation procedure
Irradiation was carried out at room temperature in aerobic conditions at the ESRF
medical beamline (ID17) (Elleaume et al, 1999). Cells were irradiated as suspension
in horizontal continuously rotating cryotubes (2 ml, 10 mm in diameter), vertically
translated up-and-down through a 500-μm-thick X-ray beam providing a dose rate calculated
in water of about 0.5 Gy s−1. Dose calibrations were performed using a cylindrical
ion chamber (PTW 31002) coupled with a Unidos® electrometer. They were cross-checked
with a high-purity Germanium detector (Eurisys Mesures®, Lingolsheim, France). Real-time
control of delivered doses was provided by a 10 cm long nitrogen filled ion chamber,
continuously present in the beam.
Energies were tuned with an accuracy of ±100 eV. The dose rate was equal for all the
tested energies, which were 32.8, 33.5, 50 and 70 keV. We point out that the K-edge
of iodine is 33.169 keV. This setting was obtained with an Si(111) fixed-exit monochromator,
designed for computed tomography with synchrotron radiation as previously described
(Suortti et al, 2000; Corde et al, 2002). The ESRF storage ring was operating in its
‘uniform mode’, providing a storage ring current decreasing from 200 to 170 mA with
a lifetime of 60 h.
Data analysis
Colonies with more than 50 cells were counted using digital images of Petri dishes
containing fixed and stained clones, associated with a computer assisted image analysis
system (Samba Technologies, Meylan, France) as previously described (Biston et al,
2003), which allows to avoid subjective bias in the procedure.
Experimental data were fitted with the linear quadratic model (LQ):
where S is the survival probability, D the radiation dose (Gy), α and β are the fit
parameters (Gy−1 and Gy−2 respectively).
Enhancement ratio
We used two different ratios to measure the dose modifications produced by the iodine.
The sensitisation enhancement ratio at ‘S%’ of survival, SERs% was calculated from
the experimental cell survival curves and defined as the ratio of doses (sensitised
to control) that yielded a given cell survival level of S%:
The theoretical expected dose enhancement ratio, DER, was calculated from the variation
of the mass energy-absorption coefficient of the target due to the presence of iodine:
where
is the mass energy absorption coefficient for the considered compound irradiated with
monochromatic X-rays beam (energy: E) and w
I is the fraction by weight of iodine in the mixture.
RESULTS
Energy dependence of the DER for different iodine concentrations in water
DER variation with photon energy has been represented in Figure 1
Figure 1
Energy dependence of the theoretical dose-enhancement ratio for several iodine aqueous
mixtures (from bottom to top, the mass proportion of iodine in water, w
I is ranging from 0.01 to 1).
from Hubble physical data references (Hubbell and Seltzer, 1997). This variation is
a bell-shaped curve having its maximum around 50 keV. The maximum DER is strikingly
increased when the iodine concentration in water is rising up to 100%, reaching about
160. The range of energies yielding such a sharp variation is rather narrow from the
K-edge of iodine (33 keV) up to about 80 keV.
Experimental energy dependence of the SER for cells irradiated with 10 mg ml−1 of
extracellular iodine in medium
Survival curves of SQ20B cells are displayed in Figures 2A–C
Figure 2
Survival curves of SQ20B cells irradiated with (open symbols) or without (closed symbols)
10 mg ml−1 iodine incorporated as contrast agent in medium, for the energies: (A)
around iodine K-edge: 32.8 keV (triangles) and 33.5 keV (reversed triangles); (B)
50 keV (squares); (C) 70 keV (circles). Each survival curve fit is derived from the
dose and surviving fraction data (triplicate experiments).
, showing the modifications of the dose–effect relationship for synchrotron radiation
of different energies with or without 10 mg ml−1 of iodine introduced as Iomeron®.
These experimental results have been obtained with a constant dose rate whatever the
energy level. It appears that the radiosensitisation is energy dependent.
The comparison of experimental SER10% with the calculated DER, according to the energy,
is shown in Figure 3
Figure 3
Comparison of the energy dependence of the calculated dose-enhancement factor (DER)
with the measured one at 10% survival level (SER10%), for 10 mg ml−1 of extracellular
iodine.
. The variation in the behaviour of both parameters with energy is similar with the
same apparent maximum at 50 keV but experimental results are constantly lower than
predicted. The experimental SER10% increases slightly when the energy goes through
the iodine K-edge (from 1.05 to 1.23), but reaches its maximum for 50 keV (1.95) and
decreases again for 70 keV as the theory predicts.
Experimental energy dependence of the SER for cells irradiated with 10 μ
M of iodine incorporated in DNA as IUdR
The same experiment was performed with iodine incorporated into the cell nucleus as
iodinated nucleotide by exposure to 10 μ
M IUdR during 48 h followed by irradiation at different energy levels. Once again,
we observed a cell sensitivity energy dependence, for the same dose rate of monochromatic
irradiation, as shown in Figures 4A–C
Figure 4
Survival curves of SQ20B cells irradiated with (open symbols) or without (closed symbols)
a 48-h pre-exposure to 10 μ
M IUdR, for the energies: (A) around iodine K-edge: 32.8 keV (triangle) and 33.5 keV
(reversed triangle); (B) 50 keV (square); (c) 70 keV (circle). Each survival curve
fit is derived from the dose and surviving fraction data (triplicate experiments).
. Similarly, 50 keV is the energy yielding the maximum cytotoxic effect. The experimental
SER10% obtained is 2.6 for 50 keV, and the difference below vs above the K-edge of
the iodine is fairly reduced, the values are, respectively, 1.25 and 1.64.
Comparison of the effects of both iodine compounds
Figure 5
Figure 5
Comparison of the energy dependence of the sensitization enhancement ratio (SER10%)
for cells pretreated with 10 μ
M IUdR for 48 h or irradiated with 10 mg ml−1 of iodine incorporated in their medium
as contrast agent.
compares the SER10% obtained with SQ20B cells irradiated at different energies with
either 10 mg ml−1 extracellular iodine or intracellular iodine incorporated into the
nucleus as IUdR. For the same survival level, namely 10%, the intracellular situation
of iodine proved to be more efficient than the extracellular case except for the highest
energy of 70 keV.
Interestingly, the comparison of survival curves from Figure 2 and 4 shows a more
deeply altered shape for intracellular iodine than for the extracellular iodine. The
initial shoulder is strongly reduced giving a high-TEL-radiation-like shape for intracellular
iodine. As an illustration, Figure 6
Figure 6
Comparison of the survival level dependence for the calculation of the experimental
factor SERS% for cells irradiated at 50 keV either with a 48 h pre-exposure to 10 μ
M IUdR (closed symbols) or with 10 mg ml−1 iodine incorporated in the medium via a
contrast agent (open symbols).
shows the variation of the SERs%, according to the survival level, measured at 50 keV.
A striking difference is observed between both iodine situations. For intracellular
iodine, the sensitisation enhancement ratio increases from 2.6 for a survival rate
of 10% up to almost 10 for 90% survival. For the extracellular iodine, the sensitisation
enhancement ratio is almost constant around 2.
DISCUSSION
The sensitivity of SQ20B cells to kilovoltage X-ray beams is enhanced in the presence
of the iodine compounds, whatever its subcellular localisation. This enhancement depends
upon the choice of the X-ray energy beam, as predicted by the theoretical DER curves
(Figure 1).
Iodine contrast agent as radiation sensitiser
When extracellular iodinated contrast agent was used, experimental values of the enhancement
ratio, estimated at 10% of the surviving fraction from the linear-quadratic interpolation
of the survival curves, was systematically inferior to the DER by a factor varying
between 23% (50 keV) to 40% (33.5 keV).
Such differences between the calculated and the experimental enhancement ratio could
be explained by different factors:
Since not all energy deposited results in cell killing, the theoretical dose enhancement
ratio will always overestimate in vitro or in vivo measurements.
The experimental working conditions are arbitrary (choice of the cell line, geometry
of the setup, cell density during irradiation).
Calculation of the theoretical factor does not take into account the experimental
geometry: a physical autoabsorption of the photoelectrons by the medium itself and
as a consequence less radiation dose seen by the cells in suspension in their medium
could be taken into consideration by finer simulations.
Finally, the survival rate level chosen for the comparison is of prime importance
as suggested in Figure 6.
Nevertheless, the shape of both the enhancement ratio variations are consistent, with
an experimental maximum at 50 keV and a minimum just below the iodine K-absorption
edge (Figure 3). Moreover, this enhanced radiosensitivity is concentration dependent,
as published elsewhere (Estève et al, 2002).
We interpret the lethal effect enhancement observed as closely linked to photoelectric
interaction on the high-Z atoms present in the vicinity of the SQ20B cells (Callisen
et al, 1979). As studied by Matsudaira et al (1980), the use of more energetic radiation,
such as γ for instance, would not imply similar results. With these energies comparable
with the ones used in radiotherapy, Compton scattering is the major physical interaction
and does not vary sufficiently with the matter composition for giving probing enhancement
factors (Robar et al, 2002). Matsudaira et al (1980) demonstrated with a 200 kVp polychromatic
(p) X-rays tube that 5% of iodine in the cell growing medium modified cellular response
to the irradiation, but no effect was shown with irradiation from 60Co.
We extrapolated their survival curve data and estimated that the SER10% factor was
equal to 2.24 for 50 mg ml−1 of iodine and 200 kVp irradiation. Dawson et al (1987)
have found similar results with an SER10% estimated from their data to be around 1.8
for 20 mg ml−1 of iodine and 250 kVp irradiation. Interpolation of their data to 10 mg ml−1
of iodine would have led to a sensitisation enhancement ratio of 1.3. This factor
has been increased to 2.25 by using a lower energy X-ray beam of 140 kVp (Iwamoto
et al, 1987; Solberg et al, 1992a). Nevertheless, this last value has not been calculated
from survival curves data, but from micronuclei formation in cells postirradiation.
These experimental demonstrations of the radiotoxicity enhancement of low- and medium-energy
X-rays due to the presence of iodinated contrast agents had some consequences in radiological
diagnosis, mainly because of the fear of mutagenic effects postexamination (Adams
et al, 1977; Norman et al, 1978, 2001). Nevertheless, the X-ray doses implied in such
examinations are not comparable with the therapeutic ones.
Based on these results, a brand new radiotherapy technique called CTRx for computed
tomography radiotherapy was put forward by Norman and collaborators. They propose
using a classical scanner (voltage 140 kVp) slightly modified for allowing field collimation,
adjustable to tumour sizes. The aim of the technique is to obtain sharp isodoses around
the tumour, using both the photoelectric effect on the high-Z element present in the
tumour and the circular irradiation ballistic (Mesa et al, 1999). Phase I clinical
trial was published for treatment of patients with metastatic brain tumours, loaded
with iodinated contrast agents, and demonstrated the feasibility of this technique
(Rose et al, 1999). The dose-enhancement effect is hence theoretically optimised with
140 kVp X-rays beams when compared with 10 MV, and, interestingly enough even in cases
of stereotactic irradiation.
However, polychromatic conventional X-ray tubes do not lead to an optimum energy deposition
inside the iodine-loaded tumour (X-ray spectrum hardening with depth). Synchrotron
X-rays beam should allow the choice of the optimal X-ray energy for energy absorption
enhancement inside the iodinated tumour compared with healthy nonloaded tissues (Solberg
et al, 1992b).
Our results show that this optimal energy does exist and according to our calculations,
its value is around 50 keV. For this particular energy, the SER10% measured on our
cell line is 2.03 for 10 mg ml−1 of iodine incorporated as contrast agent in the medium.
This sensitisation value appears to have the same order of magnitude for monochromatic
beam in comparison with the results quoted above with polychromatic beams. Nevertheless,
such comparisons have to be made carefully and are always difficult when different
cell lines are considered. It should be stressed that SQ20B cell line is particularly
radioresistant and nonapoptotic (Brachman et al, 1993).
Another advantage of the synchrotron radiation beam, for this bimodal approach, is
the imaging scanner tool, which was developed on the ESRF ID17 medical beamline (Elleaume
et al, 2000b, 2002). It allows the in vivo measurement of absolute tumoral iodine
concentrations (Le Duc et al, 2000), which is an essential parameter for planning
the doses to be delivered. This advantage is not available with other bimodal approaches:
neither with conventional scanners due to beam hardening nor for BNCT as previously
mentioned. This could be a valid argument for considering this technique for clinical
trial evaluation.
Iodine incorporated into DNA as IUdR: subcellular and energetic optimisations
5-iodo-2′-deoxyuridine was used in this study to optimise the subcellular localisation
of iodine compounds. 5-iodo-2′-deoxyuridine does not remain extracellular as contrast
agents, but directly substitutes DNA thymidine base, and is hence incorporated inside
the DNA morphology during its replication in cycling cells (Pomplun and Terrissol
1994). This compound is known to sensitise mammalian cells to damage induced by ionizing
radiation, both in vitro and in vivo. The underlying sensitisation mechanism is not
yet fully understood but could rely on alteration of the DNA structure (Iliakis and
Kurtzman, 1989) or a decrease in cell reparability (Wang and Iliakis, 1992; Wang et
al, 1994). As this compound requires a cellular proliferation activity, it has the
property to target tumours having high proliferation rates.
The photonic activation of stable iodine atoms, incorporated in DNA with IUdR, was
first proposed by Fairchild et al (1982). They calculated a sensitisation factor comprised
between 1.5 and 3 depending on the percentage of thymidine replacement. This technique
avoids the drawbacks of IUdR labelled with Auger emitters radioisotopes, which are
also toxic for healthy fast-growing tissues such as the bone marrow.
Whereas clinical use of IUdR in association with megavoltage X-rays beams brought
to reserved results (Epstein et al, 1992), photon activation therapy proposed by Fairchild
and Bond (1984) was based not only on IUdRs use but also on the idea of an energetic
optimisation of the X-ray beam too. Photoelectric absorption discontinuities of the
isolated heavy atoms lead to the conclusion that the energy just above the K-absorption
edge of iodine was the optimal one. Laster et al (1993) demonstrated, for this particular
energy, that the dose necessary to decrease the surviving V79 cells fraction to 10%
was three times less for cells pre-exposed to 6 μ
M IUdR for 14 h (16% substitution) than for the untreated cells. This value decreased
to 1.4-fold less when synchrotron X-rays energy was just below the iodine K-edge.
These are the most satisfying results yet, among a series of similar works, which
had common objectives but used different experimental methods. A sensitisation ratio
equal to 1.8 has been observed by Shinohara et al (1996) with 20% thymidine bases
substituted by iodine from IUdR and a γ-irradiation from 60Co. Another study with
137Cs irradiation and similar iodine content gave comparable results (Fairchild et
al, 1985). This factor was found to be equal to 1.5 by Nath et al (1987) with 250 kVp
X-rays.
The choice of the optimal X-ray energy for irradiating IUdR pretreated cells is investigated
in the present work, similarly to Karnas et al (1999), (2001a). Theoretical calculation
of the DER relative to the presence of 10 μ
M 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. Other authors have reported comparable
measured DNA iodine contents for exposure of exponentially growing cells. Hence, for
a 10 μ
M IUdR during a double cell cycling time (48 h), a thymidine substitution ranging
between 10 and 20% is expected (Laster et al, 1993).
Consequently, our experimental results are in good agreement with the calculations
made by Karnas et al (1999). Due to the lack of available synchrotron sources, adjustable
monochromatic beams were not used to validate their calculation, but CHO cells exposed
to 10 μ
M IUdR for 3 days and irradiated with medium energy X-ray tube (100 kVp) exhibited
SER1% of 1.8 vs 1.4 for low-energy spectrum (30 kVp). By filtrating the 100 kVp beam
with tungsten, SER1% reached a value of 2.7, corresponding to a thymidine substitution
by iodine of 18%.
With a monochromatic beam, SER10% for SQ20B cells pre-exposed for 48 h to 10 μ
M IUdR was found to be equal to 2.62 at 50 keV. This energy corresponds to the experimental
maximum of radiosensitisation. Interestingly, around the K-edge of iodine, SER10%
slightly increases by crossing the edge (from 1.25 to 1.64) but our enhancement ratios
remain low in comparison with some other published data (Laster et al, 1993). Moreover,
energies around the K-edge are experimentally found not to be optimal for increasing
the differential effect between treated and untreated cells.
Owing to the energy dependence of the sensitisation found for cells pretreated with
IUdR, it is more likely due to the photoelectric effect than to an intrinsic sensitisation
action of IUdR, for which an energy dependence could hardly be expected.
Comparison of the effects of both iodine compounds
Pre-exposure of cells to 10 μ
M IUdR for 48 h leads to greater sensitisation enhancement ratios than the presence
of 10 mg ml−1 of iodine as contrast agent in the medium (Figure 5). 5-iodo-2′-deoxyuridine
is 30% more efficient at 33.5 and 50 keV, 20% more at 32.8 keV and sensitisation ratios
appear to be the same at 70 keV. Above the K-edge of iodine, photoelectrons from the
K shell are extracted with a kinetic energy of 300, 18.8 and 36.8 keV for 33.5, 50
and 70 keV excitation energies, respectively. Reported to the nucleus and cellular
dimensions, the range of photoelectrons emitted by iodine atoms placed inside the
DNA is then less critical for the highest energies studied. The biological efficiency
of photon activated IUdR with regard to the extracellular iodine could be explained
by damages produced directly inside the DNA by Auger electrons. These low-energy electron
cascades are known to be biologically efficient and extremely toxic, but only if generated
in the nucleus or preferably in the DNA (Commerford et al, 1980; Faraggi et al, 1994;
van Dieren et al, 1996).
The effect of Auger electron cascades for IUdR can be deduced by analyzing the shape
of survival curves (Figures 4 and 6). The absence of a shoulder indicates a defect
in repair of DNA damages, which are supposed to be more complex. On the contrary,
survival curves for iodine incorporated as contrast agent do not show any loss of
shoulder and seem to indicate a simple creation of an extra number of both single
strand breaks (SSB) and double-strand breaks (DSB). For IUdR data, this leads to an
extreme dependence of the SER factor with the choice of the survival level S% used
for the calculation. The SER90% reaches a value of 9.5 around 90% of cell survival
rate, which could be worth considering for a fractionated irradiation with low dose
per fraction. On the contrary, the ratios remain similar for iodinated contrast agent,
whatever the survival level chosen. The survival curves exhibit then low-LET shapes,
indicating that in both approaches, completely different biophysical and molecular
damages are generated inside the DNA.
Some reserve has been expressed in the literature concerning the potential clinical
use of externally synchrotron-activated stable IUdR (Miller et al, 1987a, 1987b; Humm,
1988a; Humm and Charlton 1988b). Our encouraging results could certainly boost the
debate. The two new elements in the discussion could be the relative effects of both
the iodinated compounds and the choice of the optimal energy to increase the enhancement
ratios.
Other clinical applications could be found by associating a monochromatic photon source
with a heavy intratumoral element. The ideal radioisotope would be one able to optimise
interactions with the targeted heavy atom. Of course, this limits the number of (emitter–receptor)
couples to be considered, but opens the way to new source concepts (Karnas et al,
2001b). Samarium sources, which emit monochromatic 40 keV γ photons, could be used,
for instance, in association with stable iodine (Fairchild et al, 1987; Laster et
al, 1992). Energy deposited by 125I seeds during prostate brachytherapy treatment
could be enhanced by silver compounds (Young et al, 1999) or other contrast agents
like iodine, gadolinium or lutetium as well (Norman et al, 2002).
However, the synchrotron tool appears to be the most useful one for optimizing such
a concept of bimodal radiotherapy and monochromatic synchrotron radiotherapy, which
exhibits promising in vivo results (Adam et al, 2003). This concept is hence proposed
as a promising technique for optimally increasing the differential effect between
healthy and cancerous tissue irradiation.