As introduced in the previous section, there exists a multitude of interaction mechanisms on the sub-nuclear and nuclear level for heavy ions and matter, either for the primary nucleus, its fragmentation parts or secondary particles. This spectrum results in multiple ways how irradiation with heavy ions can affect a cell.
The main mechanism of action is the irreparable damage of DNA in cells that lie within the treated area. As in chemotherapy, the ability of healthy cells to repair DNA damage is superior to cancerous cells, further limiting the effects of radiation treatment on sur-rounding tissue. For this reason radiation therapy is usually given in fractions, allowing healthy tissue to recover between the treatments.
If the dose of irradiation is very high, the effect of irradiation on tissue may be seen immediately, in the form of radiation poisoning. Lower doses, as applied in therapeutical irradiation, have more subtle effects.
DNA damage
The radiobiological efficiency of charged particles is mainly characterised by their local ionisation density, which can directly be correlated to the local density of DNA damage.
Heavy ions (especially carbon) at high energies have a sufficiently low ionisation density in the entrance region, and act mainly like photons, i.e. producing mostly repairable DNA damage. Due to the particles slowing down towards the Bragg peak the ionisation density increases significantly, resulting in severe cluster damage to the DNA (see figure 10.3 for actual survival rates andScholz and Kraft (1996) for detailed description of the underlying mechanisms).
DNA damage may come in various degrees, ranging from single strand breaks (SSB) over double strand breaks (DSB) to severe cluster damage (CD). In general, SSBs can be repaired by the cell without problems due to the redundancy of the genetic code. DSBs are usually more severe events for the cell. They may result in wrong recombinations of the DNA or even complete inability of the cell to repair the damage. In that case, the cell
10 Modelling tumour therapy with hadrons
Figure 10.6: Damage to a DNA helix due to different types of radiation. While X-rays inflict only limited damage on the strands a hit with heavy ion radiation generates severe cluster damage. This is partially a result of the generation of secondary particles. Due to the fact that heavy ion radiation can be delivered very accurately this effect can be applied to fray the DNA of cancerous cell beyond repair. Source image fromhttp://www.nasa.gov/
centers/marshall/images/
content/98984main_1025SR.jpg
might use the apoptotic pathway to eliminate the potential genetic damage from the larger tissue, or it will most likely die because of damage to its protein synthesis system. If DNA damage is non-lethal for the cell, it may be passed on to the next cell generation which might eventually lead to the onset of cancer (as it is often seen in the form of secondary cancer in irradiation entry channels). Cluster damage to the DNA is most often so severe that it leads to the “immediate” death of the cell (or at least clonogenic death, through the end of mitotic activity).
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Other impact mechanisms on the cell
Besides the mechanisms for interaction of radiation with the tissue described in the previ-ous sections there are even more ways for the radiation to affect the tissue dynamics. The energy deposited in a tissue by irradiation leads to an increase in the tissues temperature.
This effect can be used within a water calorimeter to determine the absorbed dose within experiments. However, this effect does also affect the cells, since on a local scale the
in-10 Modelling tumour therapy with hadrons
crease in temperature can be quite high. Within normal tissue, heating will lead to an increase in blood flow through the tissue in order to cause cooling. The increased blood flow will also deliver oxygen into the affected area. Since the blood supply in avascular tumours is poor, the usage of blood flow to cool down the tissue is limited. This fact can be used within hyperthermia-treatment to slow down the tumour growth. In combination with sophisticated heat-delivery methods, as i.e. tumour-targeting gold-nanoparticles and microwave-heating, this approach can even destroy parts of tumours.
Another secondary effect of radiation is the production of free radicals through water radioloysis. The ionisation of water molecules leads to the creation of for example hydrogen H· and hydroxy OH· free radicals (and many others such as reactive oxygen species (ROS)). These radicals are highly reactive as they attempt to form a covalent bond. That is, they can break an existing bond within another molecule and thus destroy organic components of the cell.
Equation 10 (Reaction of a free radical)
RH+OH· →R·+H2O (10.2)
where R can be an arbitrary organic molecule.
Free radicals are cancerogenetic, but, within the context of radiation treatment, play an important part in the damaging of cancerous cells (seeDewhirst et al.(2008) andAnderson et al.(2006)).
Lack of tumour oxygenation has long been recognized as a significant factor causing resistance to radiotherapy. This decreased radiosensibility complicates the treatment with conventional radiation. Heavy ion radiation has an greatly increased effect on hypoxic tissues when compared to conventional radiation treatment, as it does not depend on radiolysis to an large extent (Kr¨amer et al.(2003)). Its high LET is a possible strategy to overcome hypoxia-induced radioresistance as it is known to be less dependent on tissue pO2.
Effect on mitochondrial DNA
As it was briefly mentioned in chapter 2, the mitochondria within the cell carry a set of genetic code called mitochondrial DNA (mtDNA) on their own (see Nass and Nass (1963)). Irradiation of cells will also affect the mtDNA with the same mechanisms that were described in the previous section.
Even though the vast majority of proteins present in the mitochondria are coded for by the nuclear DNA, this might have effects on the protein production in the mitochondria.
Effects on the mitochondria will eventually lead to defects in the cell metabolism. The effect of mtDNA-damage might be even quite pronounced, as it is known that mtDNA is particularly susceptible to oxidative damage, as mediated by free radicals. However, since
10 Modelling tumour therapy with hadrons
Figure 10.7: Microscopic visualisation of the ex-tremely localised DNA damage induced in nuclei of mammalian cells following irradiation with ac-celerated ions. Immuno-fluorescence stained repair proteins accumulate at the lesions along the indi-vidual ion tracks traversing the nucleus of a hu-man cell, appearing as parallel streaks. DNA coun-terstain (Propidium Iodide) in blue, repair protein (Mre11) in purple. Source image from www.gsi.
de/forschung/bio/dna_damage_repair.html
each mitochondrion is estimated to contain up to 10 mtDNA copies (see Wiesner et al.
(1992)), this effect might depend on multiple hits.