La radiothérapie utilise les radiations dans le but d’éradiquer les cellules cancéreuses, principalement par la génération de cassures double-brin de l’ADN. Un des effets secondaires de la radiothérapie est l’émergence de seconds cancers, préférentiellement en bordure du volume traité, où des cellules normales reçoivent un niveau de dose non létal. Ces seconds sarcomes se développent principalement après une période de latence de 3 à 20 ans. Nous avons déterminé la distribution des dommages à l’ADN (CSB et CDB) dans le champ d’irradiation et en bordure de celui-ci, après différentes conditions d’irradiations. Nous avons évalué les dommages à l’ADN et l’induction de sénescence après un traitement fractionné. La détection des foyers XRCC1 et 53BP1 par immunofluorescence a été utilisé comme marqueurs des CSB et CDB respectivement. Enfin, la sénescence a été évaluée par la mesure de l’activité de l’enzyme SA-beta-galactosidase. Nous avons également développé un modèle théorique d’évolution cellulaire, avec pour objectif le suivi des cellules après l’action d’un traitement géno-toxique, tel que la radiothérapie ou la chimiothérapie. Les caractéristiques principales de cycle cellulaire, d’endommagement et de réparation de l’ADN, et de la diffusion chimique ont été incluses. Le modèle d’évolution cellulaire est basé sur la théorie des chaines de Markov. Deux applications du modèle sont présentées (survie cellulaire et effet bystander). / Radiotherapy uses ionizing radiations in order to eradicate cancer cells mainly through the generation of DNA double-strand breaks. A side effect of radiotherapy is the emergence of second cancer, preferentially at the border of the treated volume, where normal cells receive some non-lethal leaking radiations. These second cancers are mainly sarcomas and develop with a latency of 3 to 20 years. We have determine the distribution of DNA damage (SSBs and DSBs) both in-and at the border of the irradiation field following various conditions of irradiation. We also investigated DNA damages and induction of senescence after multi-session of treatment. Fluorescent detection of 53BP1 and XRCC1 foci was used as a marker of DSBs and SSBs respectively. Finally senescence state has been tested by measurement of SA-beta-galactosidase activity. We also developped a theoretical agent-based model of cell evolution under the action of cytotoxic treatments, such as radiotherapy or chemotherapy. The major features of cell cycle and proliferation, cell damage and repair, and chemical diffusion are included. Cell evolution is based on a discrete Markov chain. Two showcase applications of the model are then presented (survival curves and bystander effect).

No description available.

The presence of a moderately strong magnetic field, uniform and static, in the irradiated medium modifies the spatial distribution of events. The imposition of a magnetic field produces elecron helices, characterised by their radii and pitches. The differential and integral distribution of track lengths, corresponding to electrons slowing down in water in a magnetic field, have been computed as function of radii and pitches for 200 kVp X-rays and for ⁶⁰ Co gamma-rays. Theoretical work has shown that the probability of energy deposition in a smaller volume of the absorbing medium has been significantly increased as a result of the presence of a magnetic field during photon irradiation. The distributions of track lengths as function of electron radii and pitches have been studied in strong magnetic fields (1 - 20 Tesla). The trajectories of an electron moving in water for different emission angles (up to π/2) and for magnetic fields of 5 and 10 Tesla, have been computed. The data for stopping powers used in this study, cover electron energies of 30 eV to 1200 keV (initial energy). In the presence of a magnetic field, each electron spiral has enclosed a conical volume. As the magnetic field increases, so the volume enclosed by the spiral decrease resulting in a substantial increase in the number of hits (events) compared with events in the same volume in the absence of a magnetic field. The experimental work started with the study of the characteristics of a spherical walled proportional counter. The frequency density, y.f(y), energy probability density, y^2f(y), distributions and their averages overline Y_F and overline Y_D respectively, have been computed on the basis of the pulse height distribution of low-LET radiation. Gamma rays from ¹³⁷Cs and ⁶⁰Co have been used with and without a magnetic field. Transverse magnetic fields of 0.0304, 0.13, 0.24 and 0.34 Tesla as well as a longitudinal magnetic field of 0.0304 Tesla have been used in microdosimetric measurements. An average sphere diameter of 2 μm has been simulated for the purpose. In the presence of the transverse magnetic fields, an increase of up to ~ 45% and ~ 78% has been obtained in the values of overline Y_F and overline Y_D respectively for ^137Cs gamma rays. For ^60Co gamma rays the values of both overline Y_F and overline Y_D increase by up to about 97%. For the longitudinal magnetic field when compared with the corresponding transversal magnetic field, a substantial increase in the value of overline Y_F has been found for ^137Cs gamma rays and a less significant increase for ^60Co gamma rays. Also, a significant increase in overline Y_D has been obtained for both indirectly ionizing radiations.

The solar UVB radiation incident on a horizontal surface was measured and related to more routinely recorded meteorological variabIes in a study of the UVB climatology of the English East Midlands. Exposure of individuals in this climate was monitored and related to vitamin D status. On clear days relations were found between the logarithm of UVB intensity lƛ and airmass µ,and at 304 nm where ozone amount [O3] is the dominant atmospheric attenuating factor a2 In Iƛ/aµa[03] was close to the ozone absorption coefficient for this wavelength. At longer wavelengths other attenuation processes have to be accounted for. Measurements of the waveband 300-316 nm were compared with irradiation over broader wavebands. On clear days the ratio of UVB to visible irradiance IB/IV was 4.16 cos z + x where z is the solar zenith angle and x is a coefficient which varies from day to day. Similar analysis for the full solar waveband IF showed a similar linearity of IB/IF with cos z for each day, but both slope and intercept changed between days. A relation between daily integrated totals of UVB and full solar radiation (300-3000 nm) was found, enabling UVB radiation to be estimated from measurements made with a standard meteorological pyranometer. The best estimates require daily figures for ozone concentration but an approximation may still be made using monthly mean concentrations or climatological averages. Diffuse UVB radiation was measured and found to be always greater than 0.5 global UVB. The shade-ring correction applicable in this region of the spectrum is ~ 0.01 greater than the geometric correction. Estimates of the anisotropy of UVB sky radiation gave the relative strength of the circumsolar region as 0.36 with an angular width of 0.78 radians. Polysulphone film was tested and found suitable for use as a personal dosimeter for solar UVB radiation. The UVB exposure of elderly long-stay hospital patients was monitored for a three month period and compared with that of a young healthy population. Plasma 25-hydroxyvitamin D concentrations were measured to assess vitamin D status and the change in plasma 25(OH)D resulting from skin irradiated with solar UVB was found to be 6.9 ± 0.4 ng J -1 for the elderly and + 7.3 ± 3.4 ng J-1 for the young volunteers suggesting little difference between the responses of the elderly and the young. The implication of these figures is that sunlight exposure: of a few hours per week is adequate to maintain a healthy vitamin D status.

The short-lived PET radionuclide (^134)La(t(_1/2)=6.7 minutes) is well suited to the repeated evaluation of blood perfusion, thus providing a method of following changes in tumour behaviour, in response to therapy. Ligands, both acyclic and macrocyclic, have been synthesised, and the complexes formed with (^134)La(^3+) evaluated in vitro and in vivo. Other lanthanide complexes have also been evaluated for potential use in magnetic resonance imaging and photoimmunoassay studies. A preliminary crystal structure determination of a lanthanum tetrabenzylphosphinate complex reveals the presence of one water molecule in the inner co-ordination sphere. The development of monoclonal antibodies with a specificity for the surface features of tumour cells presents a method for the localisation of a radionuclide at the tumour. Copper-64 (t(_1/2)=12.7 hours) uniquely combines the decay properties required for imaging and therapy. Ligands have been developed for derivatising antibody molecules with radioactive copper, whilst retaining specificity for the target antigen. Three modified proteins have been evaluated in vivo, and show a high tumour uptake compared with blood, but modest uptake compared with the liver, suggestive of some degree of protein denaturation during labelling. A more subtle approach has been developed, exploiting the affinity of biotin for avidin. Higher selectivity at much shorter post-administration time is potentially attainable by the use of a multi-step procedure. A copper binding ligand incorporating biotin has been synthesised. The (^64)Cu complex of the conjugate shows specificity for the protein avidin both in vitro and in vivo. The prognosis of patients with hepatoma or liver metastases is poor. A lipophilic copper complex has been synthesised and retention in the liver demonstrated in vivo. Measurements with three cell lines in vitro suggest that the complex is more readily taken up by tumour cells (and cells from metastases) compared to normal cells.

In this thesis, a detailed review and analysis is undertaken of the numerical and theoretical data employed in the various National and International Dosimetry Protocols and Codes of Practice currently in use. Air kerma to dose conversion factors for megavoltage photon and electron beams are then derived, using each of the protocols, for a variety of commonly used ionisation chambers and it is found that differences in the resultant values are present for both photon and electron beams. For example, for a NE2571 graphite walled cylindrical ionisation chamber, the maximum variation in the air kerma to dose conversion factor for photons <I>C_w,λ</I> occurs at a "nominal" energy of 25MV, where the difference between the maximum and minimum values of <I>C_w,λ</I>is 5.1%, while the maximum difference between the different protocols in the air kerma to dose conversion factor for electrons <I>C_w,e</I>occurs at a mean incident energy of 9 MeV, where the difference between the maximum and minimum values of <I>C_w,e</I> is 2.7%. Analysis of the conversion factors indicates that the cause of these differences is due to a combination of both the numerical data and theoretical factors employed, although the major contributions to the differences arise from the use of different sets of stopping power ratios in the different protocols; in turn the use of different sets of stopping power ratios arises partly from different methods of specifying beam quality. An experimental approach was, therefore, developed to determine the consistency of each protocol's air kerma to dose conversion factors with an absolute value for one quality of beam, i.e. the relationship to a photon calibration standard, and also to examine the consistency between photon and electron beam modalities. When Cobalt-60 gamma rays were used as a calibration quality and comparative measurements were made in photon beams of nominal energies from 6MV to 25MV, and electron beams of nominal incident energies from 5MeV to 20MeV, inconsistencies were found in the majority of protocols and, for photon beams this was found to be attributable to inadequate description of photon beam quality.

The aim of this research project was to investigate ways of improving the accuracy of dosimetric measurements in pion radiotherapy. Interest in this area was stimulated by the results of recent experimental work which revealed that materials from which dosimeters in pion radiotherapy are routinely constructed are not tissue equivalent for pi-. Two means of achieving the stated objective were identified: 1. To produce materials which are tissue equivalent for pions, to use in the construction of phantoms and dosimeters. 2. To evaluate correction factors necessary to convert dose recorded under non-tissue equivalent conditions to that for tissue. An attempt was made to produce muscle and bone equivalent phantom materials. The extent to which the materials produced could be considered tissue equivalent was judged by comparing experimentally determined carbon to oxygen (C:O) and nitrogen to oxygen (N:O) pion atomic capture ratios with those for the corresponding tissue type. Negative pion atomic capture ratios were also evaluated for sets of simple organic compounds to aid further development of the theoretical models necessary to determine correction factors.

In the fields of radiobiology and nuclear medicine there is considerable interest in the important role played by Auger electron cascades caused by inner-shell ionisation in realistic risk. It is necessary to quantify this risk when radionuclides are used on a routine basis as investigative, diagnostic and radiotherapeutic tools, whether the applications involve incorporated electron capture radionuclides or K-shell ionisation of selected stable nuclides by X-rays, as in "photon activation therapy". Relevant published survival data on biological damage caused by the internal emitters 125I, 77Br, 3H, 33P, 131I and 32P which are incorporated into the DNA of mammalian cells, bacteria (E. Coli) and bacteriophages have been collected and the results re-analysed in terms of the parameters of a new damage model to determine an inactivation cross-section for each internal emitter. These quality parameters are the absolute specification of radiation quality and are compared with cross-sections similarly determined for the effects of external radiations from heavy charged particles and photons (chapter 2). The inactivation probabilities obtained for the nuclides 125I, 77Br and 3H extend over a wide range of values depending on the type of nuclide and its distribution, the type of sensitive target and its shape and distribution, and the environmental temperature during both irradiation and post-irradiation incubation. The higher values approach those determined for heavy charged particles with the same mean free path for primary ionisation, and are an order of magnitude larger than would be expected for external irradiation with photon generated electrons. The results for 33P, 131I and 32P nuclides are appreciably smaller than that expected for external irradiation since the long range electrons dissipate most of their energy out of the sensitive target. A theoretical equation for X-ray production by accelerated electrons incident on a thick target has been revised by including factors to compensate for backscattering, direct and indirect ionisation, attenuation in the target and the incident angle of electrons (chapter 3). An electron accelerator X-ray machine capable of delivering monoenergetic photons up to ~ 4.8 gray/sec exposure dose rate from four different targets has been designed, constructed and tested (chapter 4) The biophysical mechanisms of direct and indirect radiation action has also been studied using the metallo-enzyme dihydroorotic dehydrogenase. The enzyme was irradiated both in dry state and in solution at different concentrations and at different dose rates using monoenergetic Cu-K photons from our X-ray machine. A technique was developed whereby it was possible to isolate and quantify each type of radiation action (chapter 5). The inactivation of the enzyme in both solution and in dry state was found to be a single-hit/single-target process. It was also found that in solution the inactivation of the enzyme was dose-rate-and concentration-dependent with efficiency of radical inactivation has an exponential dependence on dose-rate and the inverse of the enzyme concentration. A new model for the inactivation of the enzyme has been suggested and its parameters, namely direct and indirect cross-sections, geometrical cross-section, saturated concentration constant, root mean square diffusion constant, mean free path of radicals absorption, life time and G value of radical production, have been determined. It is expected that this model can be generalised to suit other enzymes (chapter 6).

No description available.

The technique of electron spin resonance spectroscopy was employed primarily to study the effects of ionizing radiation, in the form of x-rays (50Co source), on various organosulphur compounds, selected polyamino acids and proteins, and DNA. The work was carried out exclusively at low temperature ( 240K), powder, frozen aqueous or CD3OD/D2O deoxy glass systems being studied. The underlying principle of the work presented here was "radioprotection". To this end, several known thiol radioprotectors have been studied, along with thiol compounds where previous research has not been so extensive. The aim of this was to try to resolve a long-standing controversy in the literature which has both chemical and biochemical implications. The problem is the fate of radicals generated in the thiol "radioprotector" after it has completed its act of repair in a biochemical system. This is studied, evaluated and discussed in Chapters 2-6 and has direct bearing on the work presented in Chapter 8. The reverse of this radioprotection is discussed in Chapters 7 and 8 that is radiation damage to bio-macromolecules. Chapter 7 is concerned primarily with damage occurring via an electron-loss centre in polyamlno acids and proteins whereas Chapter 8 involves damage to the cells primary target - the DNA molecule itself.