Non-rejoining DNA breaks and cell inactivation.
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Biomedical subjects
Publications and source records attributed to D T Goodhead.
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Many mutagens are known to induce a variety of different types of lesions in DNA. Cellular repair systems may eliminate some of these; some unrepaired lesions may lead to loss of reproductive capacity and others to viable mutations. Simple considerations of these three alternative fates of an exposed cell show that there should be a linear relation between the logarithm of the surviving fraction (log S/SO) and log (1-M) where M is the mutant frequency. For low frequencies the relation assumes the simpler form M=-m log S/SO. The published literature on experimental mutagenesis in eukaryotes confirms these expectations. Observed differences in the slope m when different mutagens induce the same mutation in a given kind of cell (or a given mutagen induces the same mutation in different kinds of cell) imply that mutation and cellular inactivation do not arise from one type of DNA lesion only.
Irradiation with ultrasoft X-rays produces electron tracks of short defined lengths in the irradiated material. This property is of particular interest in distinguishing between different models of radiation action on living organisms. The production, absorption and dosimetry of aluminium K characteristic X-rays of energy 1.5 keV are described. Quantitative experiments on mammalian cells with these X-rays are possible, and they were found to be considerably more effective than gamma-rays in inactivating Chinese hamster V79 cells in vitro.
The induction of inactivation and mutation to thioguanine-resistance of two types of cultured mammalian cells, V79 Chinese hamster and HF19 human diploid, was studied after irradiation with aluminium K characteristic ultrasoft X-rays, helium ion track intersections of different LET, 42 MeV d-Be neutrons, and hard X- or gamma-rays. The form of the dose-response curves was different for the two cell-types, and there was an overall difference in radiosensitivity, the human cells being the more sensitive to all radiations. However, for both inactivation and mutation-induction, the relative responses of both cell-types to these radiations was similar. Aluminium X-rays were considerably more effective than hard X- or gamma-rays and were at least as effective as helium ions of 20-28 keV micron-1, although aluminium X-rays produce tracks of very limited range (less than about 0.07 micron). Single track effects by aluminium X-rays cannot, therefore, extend beyond about 0.07 micron, and the subcellular sites involved in inactivation and mutation cannot be greater than this dimension or else the effectiveness of aluminium X-rays would be similar to that of low-LET radiations. This observation is in contradiction to models of radiation action which require relatively large sensitive sites; for example the 'theory of dual radiation action' requires a site diameter of about 0.4 micron to explain the shape of the dose-response curves for V79 hamster cells.
Microdosimetric distributions for aluminium K characteristic ultrasoft X-rays and 4He ion tract intersections are calculated and used to analyse recent biological results obtained with these radiations. Results on inactivation and mutation-induction to thioguanine resistance of both V79 Chinese hamster cells and HF19 human diploid fibroblasts in vitro are analysed in terms of the Kellerer-Rossi "theory of dual radiation action". The small quantum energy of the aluminium X-ray photons and the very short length of the secondary electrons which they produce highlight the inadequacy of the model. It is shown that the model predicts r.b.e. values in conflict with those observed unless an additional variable is introduced, but that the introduction of such a variable creates mathematical inconsistencies. The experimental evidence is contrary to the conventional usage and basis of the model.
A high energy fast neutron beam potentially suitable for radiotherapy was built at the Harwell variable energy cyclotron. The beam line is described and results are given of physical measurements on the fast neutron beams produced by 42 MeV deuterons on thick (4 mm) and thin (2 mm) beryllium targets. With 20 muA beam current the entrance dose rate in a phantom 150 cm from the target was about 130 rad min-1 with the thick target and about 60 rad min-1 with the thin target. Therefore, it is possible to use both the thin target and the relatively large target-skin distance of 150 cm to improve depth dose for radiotherapy or radiobiology. With this arrangement the dose rate decreased to 50% at depths in the phantom of 11.3-15.4 cm, depending on the field size. The use of primarily hydrogenous materials for shielding and collimation provided beam edge definition similar to that of 60Co teletherapy units, and off-axis radiation levels of approximately 1% which compare favorably with 14 MeV deuteron-tritium generators. The copper backing of the thin target became highly radioactive and an alterative material may be preferable. Biologic characteristics of the beam are described in a companion paper.
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