Advances in cancer radiation therapy are most likely to arise through a deeper understanding of the mechanisms by which radiation interacts with cells, and the means by which such mechanisms can be manipulated. Furthermore, although it is well known that ionizing radiation is also a carcinogen, the risks associated with typical occupational and environmental exposures are still not well understood. As measurements of biological effects are difficult at low doses, much reliance is placed on the construction of damage models to predict such effects, models that ultimately must allow legislation to be developed that will mediate any perceived risks. In order to develop such models of the effects of ionizing radiation a mechanistic model of radiation action is required that is based on sound experimental data. Since damage to DNA within the cell is the major cause of cell death and mutation we particularly need to investigate the effect of ionizing radiations on DNA.
Ionizing radiations can produce a range of structural and chemical modifications of the DNA helix. Of these, double strand breaks (dsb), where both strands of the helix are broken within a few base pairs, can lead to lasting damage via the production of chromosome aberrations, mutations and ultimately cell killing. It is now known that the effectiveness of different ionizing radiations is critically dependent on the patterns of ionizations they produce on a nanometre scale, comparable with the diameter of the DNA helix. Theoretical track structure modelling is therefore being used with increasing sophistication to simulate the distinctive patterns of ionizations produced by a wide range of ionizing radiations.
Such models show us that penetrating primary radiation (i.e. energetic photons, electrons or ions) produce a significant number of nanometer sized clusters of ionization at the low energy track ends liberating a large number of secondary electrons and ions. Although the effects of high energy photons and electrons on DNA have been studied for many years, much less work has been published on the effects of such low energy electron and ions. Low energy atomic and molecular ions can be produced either directly by the ionizing radiation from the DNA or from the surrounding environment along the ionization track. Such ions undergo electron capture collisions and can also displace atoms from surrounding molecules resulting in bond-breaking and the production of molecular cations in excited states which dissociate into reactive fragments. Recent observations of damage to DNA components by 0.25 1.75 eV Da-1 Ar+ ions have shown that such low energy ions can induce structurally complex strand breaks in DNA, which are less easily repaired than the predominantly clean breaks produced directly by energetic radiation. Similarly recent research has shown that strand breaks in DNA may be initiated by secondary electrons at sub-ionization energies and are dependent upon the target DNA base identity, DNA sequence, and incident electron energy. They also showed that the probability of inducing strand breaks is one to two orders of magnitude larger for electrons than for photons of the same energy.
In studying DNA damage alone we not gain a complete picture of the effects of radiation within living tissue. Tissues are composed of intercommunicating cells of one or more types, hence damage in one irradiated cell in a tissue culture may be transmitted to a neighbouring unirradiated cell in the same or another tissue culture dish. This intriguing bystander effect is reminiscent of the well described abscopal effect in radiation therapy and to date the physical/chemical processes of both such effects are largely unknown. Thus in obtaining a fuller understanding of radiation damage it is necessary to study a broader range of structures in the cell than just those linked to DNA.
All cells whether bacterial, plant or animal are enclosed by membranes, indeed membranes make up about 80% of the total dry-matter content of animal cells. The basic structural components of any cell membrane are lipid bylayers. To date there have only been a few studies probing the effect of radiation on the cell membrane. A body of evidence has begun to emerge to suggest that ionizing radiation may have both direct (i.e. direct energy deposition within the target tissue) and indirect (through the production of chemically active secondary species such as OH radicals) effects on lipid membranes. Radiation induced changes within the lipid bilayers of the membrane may alter ionic pumps leading to either increased or decreased permeability. Such changes would result in an impairment of the ability of the cell to maintain metabolic equilibrium and can be very damaging even if the shift in equilibrium is quite small. The most extreme effects may lead to rupture of the cell membrane and thence cell death.
It is therefore important to fully characterize the mechanisms by which different types of radiation damage not only DNA but also other molecular components within the cell. This will allow models to be formulated that can predict not just the patterns of ionizations, but also the spectra of damage complexity that different types of radiation can induce.
In this workshop we plan to discuss the basic mechanisms involved in inducing radiation damage and the relationship between the amounts of energy deposited within a given region of the DNA helix/cell and the type and severity of damage that is produced. The workshop will then discuss how such data may be incorporated into mechanistic models and in turn how such models may be used to determine both protocols for clinical procedures and set radiation doses in new therapeutic treatments.
(GSF-Forschungszentrum für Umwelt und Gesundheit )
Maria Grazia Pia
(Istituto Nazionale di Fisica Nucleare)
(Consejo Superior de Investigaciones Científicas)