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Radiation Response on the Tissue Level

الكلية كلية العلوم     القسم قسم علوم الحياة     المرحلة 3
أستاذ المادة اياد محمد جبر المعموري       12/23/2011 11:17:46 AM
Lect-4-
Bioradiation

Radiation Response on the Tissue Level 1-

Up to now, radiation damage to single individual cells has been considered. An implicit assumption for many experiments is that all cells of a population can be described by the same average radiosensitivity parameters. This is not at all true when dealing with more complex tissues, which are characterized by mixtures of
different cell types and a corresponding mixture of sensitivities. The particular role of stem cells has already been described; they represent the basic important unit with respect to recovery of the tissue from externally induced injury. However, normal tissue response is often described in terms of more complex ‘functional subunits. They represent autonomous entities that are assumed to be able to regenerate from a single surviving cell, and different types of structural tissue organization are discussed. For example, the central nervous system represents an example of a so-called ‘serial’ organ, where the individual subunits are connected like the links of a chain. The damage to a single link can then already lead to serious disturbance of the organ function. At the other extreme, in parallel organized tissues the failure of a single subunit can be compensated by the function of the remaining subunits, and only when a significant fraction of subunits is inactivated will organ function be perturbed. Although the functional subunits have not yet been biologically identified in all tissues, many of the characteristic radiation effects on tissues can be explained by the above- mentioned concept, assuming that a tissue can tolerate the loss of functional
subunits up to a certain limit without detectable response. Irradiation leads to a reduction of functional subunits, and this limit thus corresponds to a threshold
dose below which no effect is visible. With increasing dose, the probability of
observing a certain level of response will increase, until for still higher doses, the
fraction of functional subunits becomes so low that the probability of observing
the effect will increase to 100%. The dose response is thus characterized by typically sigmoid curves as shown schematically in Fig. 8. However, it is not only direct damage to the functional subunits of a specific organ, but also damage to the blood vessels and the vascular structure, which might ultimately lead to a visible effect due to the corresponding disturbance of the supply with oxygen and/or nutritional factors . An important parameter directly related to the kinetics of cell proliferation is the latency period, i.e., the time interval between irradiation and the occurrence of a clinically observable tissue damage. In general, the latency period is shorter for tissues with high proliferative rate like skin and mucosa, because damage leading to the loss of the proliferative capacity is expressed early (early responding tissues). In contrast, tissues with slowly proliferating cells require longer times to express the damage (‘late responding tissues’). Furthermore, in general tissues with a high proliferation rate are more sensitive to radiation compared to the slowly proliferating tissues.

It has been shown that the response of tumor tissue to irradiation can also be
well described in terms of the stem cell concept With respect to the heterogeneity
of the cell population, hypoxic cell fractions play a particularly important
role in tumor tissues. Since many tumor types are characterized by an insufficient vascularization compared to normal tissues, they can contain substantial fractions of hypoxic cells. Due to the significantly increased resistance of hypoxic as compared to oxic cells, this cell fraction ultimately determines the probability of tumor cure. Studies of tissue effects are usually based on animal (in vivo) experiments. Because of ethic reasons, and the considerable efforts to perform animal experiments, several experimental in vitro systems have been developed to mimic typical tissue effects as closely as possible. These comprise comparably simple systems based on a three-dimensional growth pattern distinct from the conventionally used monolayers of cells up to quite complex systems with coculture of different cell types or utilizing the differentiation capacity of cells in vitro, leading to highly structured and compartmentalized 3D-cell systems

2-Biological Effects of Ion Irradiation
This section first reviews the basic systematics of ion irradiation effects on single
cells. The dependence of the biological effectiveness on dose, ion type, LET, and
the influence of the cell type will be described. All effects will be discussed with respect to the particular physical characteristics of ion beams, i.e., track structure. The discussion includes description of the influence of environmental factors such as, e.g., oxygen supply. In addition, some recent results regarding the direct visualization of the extremely localized biological action of charged particles will be presented

2-1 The Relative Biological Effectiveness (RBE):

systematic studies have been performed only after accelerators became an important tool for nuclear physics studies and could then be used also as radiation source for radiobiological applications A typical survival curve as obtained after irradiation of Chinese hamster cells with low energetic carbon ions in comparison with the dose response curve after photon
irradiation. Two essential differences are clearly visible:

1-Cells respond significantly more sensitive to carbon irradiation compared to
photon irradiation, i.e., carbon ions show an enhanced biological effectiveness
compared to photons.
2- The shape of the survival curves differs considerably. Whereas for photon irradiation the typically shouldered shape is observed, low energy carbon irradiation leads to an approximately linear dose response curve.



2-2 Systematic of RBE

2-2-1 Dose Dependence
Due to the different shape, the survival curves cannot be simply transformed into
each other by a common scaling factor applied to the dose values.

2-2-2 Energy/LET Dependence
The increased RBE is not unique for all different kinds of charged particle radiation. Instead, it strongly depends on the particular physical characteristics of the ion beam as determined, e.g., by the energy and LET of the particles under consideration.

2-2-3 Particle Dependence
Although often assumed to represent the essential parameter, LET is not suitable
to define uniquely the increased biological effectiveness of charged particles as figure below.


2-2-4 Cell Type Dependence
One important aspect of RBE is that it is not solely determined by the physical
properties of the ion beams; the biological characteristics of the particular cell type under consideration also plays a key role.
These genetic differences lead to correspondingly different radio sensitivities after X-irradiation: whereas XRS cells are most sensitive and show an almost linear dose response, V79-cells(lung fibroblasts) are most resistant, and their dose response is characterized by a pronounced shoulder. In contrast, the dose response curves for high-LET radiation become very similar, and only minor differences are observed between XRS and V79 cells However, due to the differences observed for the reference( photon) radiation, RBE values are different for three cell lines, despite their similarity of response to high LET radiation. Whereas V79 and CHO (ovary cells)cells show a significantly enhanced RBE, for XRS cells almost no increase of RBE is found, although the physical characteristics of the charged particles is exactly the same as for the experiments with V79 and CHO cells. However, the XRS cells share the tendency of decreasing RBE for LET values above 200–300 keV/?m with the other cell types.
The explanation for the missing increase of RBE is not as obvious, because at
first glance one should expect that the same arguments concerning the increased
ionization density within the tracks should hold true for all cell types. However, it has to be kept in mind that an essential part of the explanation was the expected increased complexity of the damage induced by high ionization densities, which are more difficult to repair. If, however, a cell shows a deficiency related to damage repair, increased complexity might not transform into increased effectiveness, since already non-complex damage cannot be repaired.



3- The Role of Increased Ionization Density
The explanation of the systematic of RBE and s as a function of particle energy
and LET were largely based on arguments concerning ionization density. Increased ionization density was assumed to lead to more complex and thus less reparable damage. Although plausible, these arguments need of course further confirmation from experimental data


3-1 Double Strand Break Induction and Rejoining
Intuitively one would expect the increased ionization density to lead to a higher
yield of severe damage, e.g., DSB. Surprisingly such a higher rate of DSB production has not been found; RBE values for DSB induction are very close to one even in LET-regions where the RBE for survival is significantly enhanced


3-2 Chromosome Aberrations
Investigation of chromosome aberrations also revealed the influence of radiation
quality on the rate of rejoining and repair of DSB. For example, the yield of exchange type aberrations, requiring rejoining of chromosome fragments induced by at least two DSB in two chromosomes, is significantly smaller for high-LET radiation than for low-LET radiation. Complementarily, the rate of chromatid breaks is considerably enhanced. In contrast, after conventional X-irradiation, the damage is distributed homogenously throughout the nucleus, so that the involvement of many chromosomes is much more likely, leading also to the higher rate of exchange type aberrations between different chromosomes

3-3 Fractionated Irradiation
Further evidence for the severity and complexity of high-LET induced damage
comes from studies of fractionated irradiation. Here, the total irradiation dose is
given in two or more fractions with a certain time interval in between. During this time interval, cells are incubated under optimal conditions, so that at least part of the damage can be repaired, leading to an overall decreased effect of fractionated compared to single dose exposure.

3-4 Direct Visualization of Localized Damage
More recently, new methods have been applied to visualize directly the localized
damage induced by particle radiation. These methods are based on immunofluorescent staining of nuclear sites containing proteins involved in DNA repair. Accumulation of these proteins is thought to be an indicator of particular severe and probably irreparable damage as figure below which described Visualization of the localized DNA damage by immunofluorescent methods






.


3- 5 Bystander Effects
The term ‘bystander effect’ is used to describe situations where not only the primarily damaged cells respond to radiation, but also neighboring cells show a response without being directly damaged. The bystander effect could also
explain at least partially the hypersensitivity observed after irradiation with
charged particle beams at very low doses

3-6 Tissue Effects
The above-mentioned bystander effects are expected to be of importance for understanding the response of tissues to radiation injury, because cells in a tissue are usually connected by complex communication networks. In fact there are first indications that bystander effects cannot only be detected in in vitro systems, but also in in vivo-like systems such as, e.g., tissue explants Since bystander effects play a role at low doses and low fluences, they might be in particular relevant for studies of mutation and transformation related to radiation protection. For applications of ion beams in tumor therapy, doses and thus fluences are usually comparably high, so that the fraction of unhit cells is small.


























































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