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Models of Biological Action of Heavy Charged Particles

الكلية كلية العلوم     القسم قسم علوم الحياة     المرحلة 3
أستاذ المادة اياد محمد جبر المعموري       12/23/2011 11:32:38 AM
Lecture -5-
Bioradiation

Models of Biological Action of Heavy Charged Particles 1-
The progress in experimental studies is complemented by the development of biophysical models to describe radiation effects. Modeling plays an important role for the mechanistic understanding of radiation action as well as for practical applications in radiation protection and radiotherapy. This section will thus give a brief overview over some basic concepts developed in particular to describe the biological action of heavy charged particle beams.

1-1 Theory of Dual Radiation Action
For low LET irradiation, one of the most prominent features is the shoulder shape of the corresponding dose response curves. One possible explanation of this shape is the interaction of sublethal damage, resulting in lethal damage. Since the interaction probability increases with the density of sublethal damage, higher dose lead to a higher interaction frequency and thus higher efficiency compared to lower doses, resulting in the shoulder shape of the dose response curve. Based on the analysis of chromosome aberrations, Neary has developed one of the first models specifically based on lesion interaction. Estimates revealed that interaction should take place over distances of typically micrometers, so that the distribution of damage on a micrometer scale was thought to be of particular importance. Since the spatial distribution of damage cannot be investigated directly, the spatial distribution of energy deposition was taken as a measure reflecting the damage distribution. Among others, the theory of dual radiation action (TDRA) is one of the best known models based on detailed considerations of damage interaction.

One particular aspect, which has to be considered in treatment planning, is the
tissue dependence of RBE. RBE of different normal tissues or tumors might be different,
and therefore the therapeutic gain of charged particle beams will be ultimately
defined by the particular combination of tumor type and normal tissue.
According to the radiobiological considerations

slow growing,
resistant tumors are expected to show the most significant benefit from high LET
radiation. In addition, tumors with considerable fractions of hypoxic cells represent
the second major class of tumors taking advantage of high LET radiotherapy.

1-2 Cluster Models
Progress in experimental techniques for investigation of molecular details of radiation damage revealed that thinking in terms of ‘simple’ double strand breaks as relevant lesion would be inadequate for a detailed understanding of radiation action. Clusters of damage should then result from clusters of energy deposition, and thus several models have been developed which are particularly based on detailed investigations of cluster properties of high-LET radiation with nanometer resolution.


1-3 Amorphous Track Structure Models
The above-mentioned disadvantages are bypassed in another class of models
called ‘amorphous track structure’ models. The two key features of these models
are:
A-They make use of the particular features of track structure in a certain simplified
form, in that they use only the information about the radial dose profile
D(r), but explicitly neglect the stochastic properties of secondary electron emission.
B- They are based on the assumption that no principle difference between the biological actions of low- and high-LET radiation exists, because in both cases the biological effect is due to the action of the secondary electrons. Thus, it should make no difference with respect to the biological action, whether an electron is produced by a primary photon or by a charged particle; the biological effect should be simply determined by the total amount of energy deposition in a certain, appropriately sized subregion of the cell. The basic idea of the approach is schematically shown in below figure The cell nucleus, represented by the circular area, is assumed to be the critical target for cellular effects, and a homogenous distribution of sensitivity throughout the nucleus is assumed as a first approximation.


Clusters of damage should then result from clusters of energy deposition, and
thus several models have been developed which are particularly based on detailed
investigations of cluster properties of high-LET radiation with nanometer resolution.


At the present stage, the predictive capacity of these models is essentially
restricted to the initial phase of strand break induction. Application to
more complex endpoints like, e.g., cell inactivation yields only qualitative agreement
and would require a detailed modeling of the subsequent damage
processing of the initial damage. This, however, seems not to be feasible due to the
enormous complexity of the signaling pathways involved in damage processing,
which also depend very much on the particular cell or tissue type under consideration.

5.3
Amorphous Track Structure Models




The cell nucleus is virtually subdivided into small compartments, and for a given set of impact parameters the average dose deposition in each compartment is determined from the corresponding radial dose profiles of individual tracks. From the local dose at a given position, the local biological effect is calculated from the effect observed for photon irradiation at the same dose.



2- Influence of Target Structure
The model described above is based on the assumption that lethal damage corresponds to point-like events, where point-like is meant in a biological sense, i.e., a point corresponds to the size of the smallest relevant biological structure, assumed to be the DNA strand and thus a size of a few nanometers. The critical, sensitive target for inactivation, i.e., the DNA, is assumed to be homogenously distributed throughout the cell nucleus, and no specific substructure has been assumed. The situation is entirely different when dealing with other biological endpoints like, e.g., induction of chromosome aberrations. Here, interaction of damage on different chromosomes plays the dominant role, and therefore details of the distribution of chromosome territories within the nucleus have to be taken into account Frequently the structure of a chromosome is simulated by a random walk polymer chain model. Given the appropriate boundary conditions, this leads to a relatively

The cell nucleus is virtually subdivided into small
compartments, and for a given set of impact parameters the average dose deposition
in each compartment is determined from the corresponding radial dose profiles
of individual tracks. From the local dose at a given position, the local biological
effect is calculated from the effect observed for photon irradiation at the same
dose. This requires an appropriate scaling according to the ratio of the small compartment
volume and the total sensitive volume.

compact chromatin organization in the centromere region of a chromosome and a more sparse distribution in the outer regions .As a consequence, this leads to a significant overlap and intermingling of DNA from different chromosomes.

3- Application of Charged Particle Beams in Tumor Therapy
The basic advantages of charged particle beams such as, e.g., carbon ion beams as compared to conventional photon and electron beams are the inverted depth dose profile and the increased biological effectiveness. Besides the general physical and radiobiological properties as described in the previous sections, some additional specific aspects for the application to tumor therapy will be described here. These include technical aspects of, e.g., beam delivery as well as radiobiological considerations.



4- Clinical Aspects of Radiation

First applications of charged particle beams in tumor therapy were all performed at accelerators constructed for fundamental research in nuclear and particle physics Only in the last decade the first fully hospital based treatment facilities were built in Loma Linda (USA) and Chiba (Japan). Extension of the charged particle radiotherapy program is particularly supported in Japan; several other facilities are planned there or are already under construction Whereas all of these facilities use passive beam delivery techniques, at PSI (Villigen, Switzerland) and GSI (Darmstadt, Germany) the first active beam delivery systems have been successfully tested and are now used routinely for patient treatments with protons (PSI) and cjjharbon ions (GSI). Both facilities are installed at accelerators constructed for fundamental research, with no direct clinical environment . Patient numbers are limited due to the basic research programs performed at these accelerators. At GSI, more than 100 patients with slow growing tumors in the head and neck region have been treated up to now. Since results are very promising so far, the installation of a dedicated clinical heavy ion therapy facility is planned at the Heidelberg University Clinics, and beginning of construction of the facility is expected for fall 2002. This facility will allow approximately 1000 patients to be treated per year and can deliver different ion beams in the range from protons up to oxygen ions. It is thus ideally suited for adaptation of the treatment according to a biological optimization, taking into account the particular relative biological effectiveness for the tumor tissue and the surrounding normal tissue, respectively


The situation is different in the case of proton beams. Although the principle of
superposition of Bragg peaks to achieve a homogenous dose distribution over extended
volumes is the same for protons and heavier ions, protons in general show
significantly lower RBE values compared to carbon ions. Only for energies below
10 MeV is a significant rise of RBE observed

Transferred to the
situation of superimposed Bragg peaks, this should lead to significantly enhanced
RBE values only at the very distal part of the extended Bragg peak. Therefore, in
general, RBE values of 1.1 are used for correcting physical dose values to biological
effective dose values in proton therapy without considering any dependence of
RBE with dose, tissue type, and position in the treatment field

This is in contrast to the case of heavier ions, where the estimation of the increased
RBE values is a prerequisite for the safe application of ion beams in tumor
therapy. Different approaches to take the increased efficiency into account in treatment
planning for high-LET beams are reported in the literature, ranging from experimentally
oriented approaches to methods based on biophysical modeling
[142,

5- Summary and Perspective
The characteristic radiobiological properties of ion beam radiation as compared to photon radiation can be explained in terms of their particular physical properties in combination with the potential of the biological object to process and repair radiation induced damage. The highly localized energy deposition of charged particles leads to complex types of damage, which are more difficult to process and repair. For cells which are able to repair the less complex damage induced by photon radiation to a large extent, the higher complexity of damage induced by charged particles is expressed as a higher biological effectiveness, i.e., lower doses are required to achieve the same effects compared to conventional radiation. Depending on the particles atomic number and specific energy, the ionization density within the track and thus damage complexity can be varied substantially. Charged particle beams thus represent a unique tool to study the influence of damage complexity on the biological response to ionizing radiation. Despite the extensive studies performed in the last decades, the molecular structure of damage leading, e.g., to cell lethality is not yet known. However, there is probably no unique answer to this problem, because the consequence of a certain primary damage critically depends on the potential to process and repair damage and thus depends on cell type and the genetic predisposition of a cell. Besides the complexity of damage induced by charged particles, the restriction of damage to defined subnuclear regions in particular at low particle energies represents a unique tool to study the spatial aspects of the cellular response to DNA damage. The importance of these aspects is reflected in the significantly growing interest in microbeam facilities, which allow the directed irradiation of defined subcellular and subnuclear regions with high precision.



The increased relative biological effectiveness of charged particles with respect
to, e.g., cell killing is restricted to the lighter particles; for heavier particles, saturation effects lead to a corresponding reduction of RBE. An optimal efficiency of cell killing is observed for particles in the range from helium to carbon at low energies and can be exploited in charged particle tumor therapy. However, due to the complex dependencies of RBE on tissue type and biological endpoint, this optimum is not uniquely defined but depends on the particular combination of tumor tissue and normal tissue. Future research will thus focus on individual optimization with respect to the above-mentioned parameters and will accompany the growing interest for applications of charged particle beams in tumor therapy.
















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